Epigenetic modifications in early stage lung cancer: pathogenesis, biomarkers, and early diagnosis.

INTRODUCTION

Lung cancer, a leading cause of cancer‐related mortality worldwide, poses a significant threat to public health. According to National Cancer Report 2024, lung cancer is responsible for around 1.1 million new cases and 0.74 million deaths in 2022, 1 highlighting its devastating impact. 2 Lung cancer is divided into small cell lung cancer (SCLC) and non‐small cell lung cancer (NSCLC). NSCLC includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Among these, NSCLC accounts for 80–85% of cases. However, compared with NSCLC, SCLC, characterized by small cell size, rapid growth, and early metastasis, typically has a poorer prognosis with a lower 5‐year survival rate. 3 The key to effective treatment and improving survival rates lies in early detection. Yet, the early stages of lung cancer often go unnoticed due to a lack of understanding about its initial progression, with more than 80% of cases diagnosed at an advanced stage. 4 This is one of the reasons why lung cancer continues to have such a high mortality rate. Therefore, it is crucial to intensify research into the early mechanisms of lung cancer and develop effective screening and diagnostic methods to lower mortality rates. 5 Recently, the focus has shifted to the role of epigenetics in the early stages of the disease. As research into early‐stage lung cancer progresses, it has been discovered that in addition to genetic mutations, epigenetic changes are also closely associated with the development of NSCLC and may even become the main factor in early‐stage lung cancer. 6 Because epigenetic changes occur earlier than genetic mutations, they hold significant potential as biomarkers for the diagnosis of early‐stage lung cancer. 7 Although epigenetic modifications are common in lung cancer, their impact on the early progression of the disease is still not well understood, making this an area of keen scientific interest.

Although the treatment and diagnostic techniques for early‐stage lung cancer have evolved from simple chest X‐rays in the early 20th century to advanced computed tomography (CT) scans, positron emission tomography (PET) scans, and MRI technologies, these methods still have limitations in sensitivity and specificity for early‐stage lung cancer. 8 Despite the introduction CT by Godfrey Hounsfield in the 1960s and the subsequent development of PET scans and MRI, which improved resolution of lung structures, 9 these technologies are still limited in detecting small tumors and precancerous changes, and they are costly and complex to operate. For example, although low‐dose CT has improved the detection of early‐stage lung cancer in screening, it still poses risks of overdiagnosis and unnecessary interventions. Entering the 21st century, the development of molecular biology techniques has made liquid biopsy and genetic sequencing important diagnostic tools supporting personalized treatment. 10 Liquid biopsy is a noninvasive diagnostic method that detects cancer by analyzing tumor DNA and other biomarkers in the blood. In combination with epigenetic markers, especially DNA methylation, liquid biopsy has shown significant potential in the detection of early stage lung cancer. Epigenetic modifications such as DNA methylation and histone modification occur very early in the development of lung cancer, often preceding traditional genetic mutations, providing new biomarkers for early diagnosis. 11 The DNA methylation patterns of patients with NSCLC can serve as effective markers for early diagnosis and prognosis assessment. 12 Detection of epigenetic markers can noninvasively reveal the presence of lung cancer and provide critical information about the potential development pathways and treatment responsiveness of tumors, 13 which is significant for designing more effective personalized treatment strategies. Moreover, early‐stage lung cancers have a lower frequency of genetic mutations while epigenetic modifications appear earlier, potentially serving as the primary cause of early‐stage lung cancer and promising molecular markers for early diagnosis, promoting the development of early diagnostic methods. 11 Additionally, reversing abnormal epigenetic changes has become a potential strategy for treating cancer. Many compounds targeting enzymes regulating histone acetylation, histone methylation, and DNA methylation have been developed as epigenetic therapies, some of which have shown efficacy in hematologic malignancies and solid tumors. 14

This review discusses the promising application of combining liquid biopsy with epigenetic markers in the early diagnosis of lung cancer, showcasing significant developmental potential. Researchers have focused for decades on epigenetic modifications during the DNA templating process, including DNA methylation, histone modifications, noncoding RNA (ncRNA), mRNA, and epigenetic changes within the tumor microenvironment (TME), all of which play critical roles in cancer progression. Notably, epigenetic alterations within the TME not only impact tumor immunogenicity but also regulate immune cells involved in antitumor responses. Current clinical data indicate that liquid biopsy detection of DNA methylation can predict cancer occurrence up to 4 years in advance, demonstrating that these epigenetic alterations usually precede common genetic mutations and are effective therapeutic targets. Moreover, although epigenetic regulators may need to maintain the expression of certain key target genes in tumor therapy, broadly targeting these factors could disrupt cellular balance, leading to cellular catastrophe. Therefore, this review not only explores the prospects of using liquid biopsy and epigenetic markers in early lung cancer diagnosis and treatment but also highlights the main challenges faced by this approach, emphasizing the necessity for further research to optimize treatment strategies and ultimately achieve personalized medicine and precision therapy (Figures 1 , 2 ).

DEVELOPMENT OF EARLY‐STAGE LUNG CANCER

The progression of lung cancer from atypical adenomatous hyperplasia (AAH) to minimally invasive stage IA is a critical stage in the early development of lung cancer, 15 involving multilevel biological changes and interactions among molecular signaling pathways. AAH, as a potential precursor to lung cancer, is characterized by mild to moderate cellular atypia and these cells are primarily confined to the alveolar walls. 16 At this early stage, the activation of the Wnt/β‐catenin pathway is crucial, as it promotes the accumulation of β‐catenin in the nucleus and activates the expression of genes such as cyclin D1 and c‐myc, thereby driving the cell cycle progression and cell proliferation. 17 As the lesion progresses to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma, mutations or overexpression in the epidermal growth factor receptor (EGFR) pathway also begin to show their significance. 18 , 19 These changes lead to enhanced cell proliferation and survival signals, further promoting tumor growth and progression. Additionally, epigenetic regulatory mechanisms, especially changes in DNA methylation and histone modifications, start to play a more prominent role at this stage. 20 , 21 High levels of DNA methylation may lead to the silencing of key tumor suppressor genes, 22 while changes in histone acetylation and methylation affect the structure of chromatin and gene expression. 23 The TME, including the extracellular matrix around the tumor, immune cells, and tumor‐associated fibroblasts, provides necessary support and protection for the tumor. 24 Remodeling of the extracellular matrix through the regulation of matrix metalloproteinases (MMPs) provides a physical pathway for the invasion and spread of tumor cells. 25 Moreover, immune cells such as tumor‐associated macrophages contribute to a tumor‐promoting state in the TME by secreting proinflammatory and progrowth factors. 26

Therefore, a deeper understanding of the specific roles and regulatory mechanisms of the Wnt signaling pathway in early‐stage lung cancer, especially at the molecular and epigenetic levels, is crucial for revealing the cellular and molecular mechanisms of early lung cancer development. This knowledge also provides important molecular targets for the development of targeted therapies aimed at this pathway, potentially improving treatment strategies and enhancing the survival rates of patients with early‐stage lung cancer.

Molecular and cellular changes in early lung cancer

The formation of lung cancer fundamentally represents a complex transition from normal cells to cancerous cells. In the development of early‐stage lung cancer, the transformation from pre‐malignant lesions to carcinoma is critically decisive. Specifically, during the progression from AAH to AIS and minimally invasive adenocarcinoma, numerous molecular markers exhibit significant changes. 27 These markers include key components of the Wnt/β‐catenin and EGFR signaling pathways, 28 whose activation propels the entire process from cell cycle progression to cell proliferation. 15 The activation of these signaling pathways not only promotes cellular growth but also enhances the tumor cells capacity to resist apoptosis, thereby further driving tumor growth and progression.

In different subtypes of lung cancer, these molecular alterations confer distinct genetic and phenotypic characteristics. For instance, lung adenocarcinoma (LUAD) often demonstrates mutations or overexpression of EGFR, 29 while lung squamous cell carcinoma may exhibit alterations in gene expression related to keratins. 30 SCLC is characterized by frequent inactivation of genes associated with neuroendocrine differentiation, such as RB1 and TP53. 31 These features suggest that the different subtypes of lung cancer may originate from various types of lung stem or progenitor cells, each following a distinct developmental trajectory and exhibiting different therapeutic responses.

Furthermore, the application of large‐scale parallel sequencing technologies has enabled the precise identification of genetic mutations closely associated with the development of lung cancer. These genetic discoveries not only provide new insights into the mechanisms of lung cancer formation but also propel the development of therapeutic approaches targeting specific molecular markers. For example, targeted therapies against EGFR mutations have become a crucial component of NSCLC treatment, significantly improving the survival rates of specific patient groups. This strategy of treatment based on molecular markers offers more personalized and effective options for early‐stage lung cancer, potentially enhancing the prognosis and quality of life for patients with lung cancer.

Role of epigenetics in early tumorigenesis

In the field of oncology, significant progress has been made in epigenetic research. Epigenetic modifications play an important role in the development of lung cancer. The identification of epigenetic diagnostic and prognostic biomarkers as well as epigenetic‐based therapeutic approaches are becoming hot research topics.

DNA methylation plays a crucial role in suppressing gene activity and maintaining genomic stability by inhibiting recombination events between repetitive sequences. 32 The silencing of inhibitors or the increased expression of activators caused by DNA methylation is a common mechanism for abnormal activation of the Wnt pathway. 33 , 34 Given the regulatory effects of DNA methylation on the Wnt signaling pathway, drugs targeting DNA methylation (such as DNMT inhibitors) and those targeting the Wnt pathway are effective in inhibiting tumor progression. Histone modification is another important aspect of epigenetic regulation, affecting the expression of oncogenes through mechanisms such as acetylation, deacetylation, and methylation, thereby leading to lung cancer. 35 , 36 Acetylation modifications promote gene expression by opening chromatin structures, allowing transcription factors to more easily bind to promoter regions, which sustains activation of the Wnt pathway in lung cancer cells, further promoting tumor proliferation and aggressiveness. 37 , 38 Due to the significance of histone modifications in regulating the Wnt signaling pathway, drugs targeting histone modification enzymes including HDACs, HATs, and HMTs are considered to have potential therapeutic value. 39 , 40 In the development of early‐stage lung cancer, ncRNA plays a critical regulatory role by finely tuning the expression and activity of specific factors within key signaling pathways. These ncRNAs, including microRNA (miRNA), long ncRNA (lncRNA), and circular RNA (circRNA), significantly regulate tumor behavior and its microenvironment through multiple pathways affecting cell proliferation, migration, invasion, and apoptosis. 41 , 42 In terms of drug development, research on ncRNA has shown potential therapeutic prospects. For instance, miRNA‐based treatment strategies, including the development of synthetic miRNA mimics or anti‐miRNA oligonucleotides, are currently being developed to restore or suppress the function of specific ncRNAs, regulating key pathways in lung cancer. 43 , 44 These therapies have demonstrated potential in preclinical studies and early clinical trials, especially for patients with specific ncRNA expression abnormalities. 45 , 46 The expression patterns and regulatory mechanisms of mRNA are crucial for understanding the pathogenesis of tumors. In particular, the roles of mRNA in regulating the Wnt/β‐catenin and PI3K/Akt/mTOR pathways are significant. 47 , 48 Overexpression of β‐catenin mRNA observed in many early‐stage lung cancer samples leads to sustained activation of the Wnt signaling pathway, promoting cell proliferation and inhibiting apoptosis, thereby supporting tumor development and spread. 49 , 50 Its widespread use in targeted therapy, the detection and analysis of mRNA expression have become important research tools. 51 The TME plays a critical role in the progression of early‐stage lung cancer, particularly the roles of macrophages, exosomes, and T cells in regulating tumor behavior and the interactions between lung cancer cells and surrounding cells. 52 , 53 Exosomes released by lung cancer cells are rich in miRNAs that can activate or inhibit the Wnt signaling pathway, thereby affecting lung cancer cell behavior and microenvironment regulation. 54 The close connection between ncRNA and the TME allows targeting specific miRNAs and lncRNAs to significantly influence the behavior of macrophages and T cells in the TME, 55 thereby regulating the development of lung cancer. Therefore, utilizing epigenetic modification factors in the TME as biomarkers for detecting early‐stage lung cancer has become a current research focus.

LIQUID BIOPSY AND EPIGENETIC BIOMARKERS IN EARLY LUNG CANCER DIAGNOSIS

Liquid biopsy techniques

Liquid biopsy, valued for its simplicity, speed, noninvasiveness, repeatability, and real‐time monitoring capabilities, is widely regarded as a potent tool for the future of early lung cancer screening and diagnosis. 56 This technique identifies tumor occurrence and progression information by analyzing tumor cells or nucleic acids in bodily fluids, including blood, urine, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, and pleural effusion. 57

The integration of epigenetic biomarkers, such as DNA methylation, has shown significant promise in enhancing the prospects of early lung cancer diagnosis. Liquid biopsy utilizes components like circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes from bodily fluids to detect genetic and epigenetic alterations specific to tumors. 58 , 59 These alterations, especially patterns of gene methylation which occur in the promoter regions of tumor suppressor genes or oncogenes, provide highly sensitive and specific methods for early diagnosis. For instance, studies have demonstrated that the combined methylation analysis of SHOX2 and RASSF1A in bronchoalveolar lavage fluid significantly enhances overall diagnostic accuracy compared with traditional cytological examination and serum biomarkers like carcinoembryonic antigen. 60 Moreover, the relative stability of DNA methylation allows for its detection in noninvasive samples, offering a more precise approach for early screening and diagnosis.

Another crucial component of liquid biopsies is exosomes, small lipid bilayer vesicles generated by cells through an endocytosis–fusion–exocytosis mechanism, measuring approximately 30–100 nm in diameter. 61 These vesicles, which are more abundant in the bodily fluids of lung cancer patients compared with healthy individuals, serve as carriers for intercellular material and information exchange. 62 Exosomes maintain intracellular homeostasis and transfer DNA, mRNA, ncRNAs, and proteins. These molecules play pivotal roles in promoting TME formation, enhancing tumor invasiveness, mediating immune escape, and inducing therapeutic resistance. 63 Thus, investigating the potential mechanisms of exosomes in tumor development could provide new insights for early diagnosis, prognosis, and resistance evaluation of lung cancer.

With the rapid development of genomics, transcriptomics, proteomics, and other multiomics integrations, alongside the application of high‐throughput sequencing technologies, liquid biopsy is poised to delve deeper into biological information, offering more accurate early lung cancer diagnoses and tailored treatment plans. By leveraging these advanced technologies, liquid biopsy not only improves early detection and prognostic assessment of lung cancer but also contributes to the realization of precision medicine, ultimately enhancing survival rates and quality of life for lung cancer patients.

Epigenetic biomarkers

DNA methylation

DNA methylation, a key epigenetic modification, primarily occurs in the cytosine of CG dinucleotides, forming 5‐methylcytosine. Catalyzed by DNA methyltransferase using S‐adenosylmethionine, it leads to methylation of up to 90% of CpGs in the genome, with unmethylated CpGs clustering in CpG islands (CGIs) at gene promoters and transcription start sites. 64 , 65 Lung cancer often features aberrant DNA methylation, including both hypo‐ and hypermethylation, impacting gene expression and contributing to cancer progression. 66 , 67

DNA methylation plays a crucial role in suppressing gene activity and maintaining genomic stability by inhibiting recombination events between repetitive sequences. The silencing of inhibitors or the increased expression of activators caused by DNA methylation is one of the common mechanisms for the abnormal activation of the Wnt pathway. 68 For example, the promoter methylation of genes such as those in the DKK family (e.g., DKK1, DKK3), the SFRP family (e.g., SFRP1, SFRP2), 69 , 70 and WIF1 (Wnt Inhibitory Factor 1) can lead to their downregulation or silencing, thereby lifting the inhibition on the Wnt pathway and causing its abnormal activation, which in turn promotes the proliferation and survival of tumor cells. 71 , 72 In some cases, positive regulators in the Wnt signaling pathway may be activated due to hypomethylation or other mechanisms. Increased expression and activity of β‐catenin lead to the sustained activation of the Wnt signaling pathway, promoting the proliferation, invasion, and metastasis of tumor cells. 73 Given the regulatory effects of DNA methylation on the Wnt signaling pathway, drugs targeting DNA methylation (such as DNMT inhibitors) and those targeting the Wnt pathway may be effective in inhibiting tumor progression. Research is also exploring how to reverse these methylation changes to restore normal regulation of the Wnt signaling pathway (Figure 2 ).

Hypomethylation

Like many cancers, lung tumors are particularly prone to widespread hypomethylation, especially targeting repetitive sequences such as SINEs, LINEs, subtelomeric repeats, and segmental duplications. 74 , 75 This reduction in methylation at LINE‐1 is linked with poorer outcomes and is observed even in the absence of mutations in key driver genes of LUAD. 76 , 77 While hypomethylation at transcriptional regulatory elements is less common than hypermethylation, it nonetheless has the potential to activate oncogenes. For instance, the demethylation of CGIs within the SNCG gene correlates with its heightened expression observed in various solid tumors, including lung cancer. 78 Studies also indicate that SNCG is involved in the migration and invasion of cancer cells. 79 Similarly, research shows that MAGE genes, upregulated in 41.8–46.3% of NSCLC tumors and carcinogen‐affected lung epithelial cells, are also associated with a loss of methylation. 80 Overexpression of these genes is crucial for tumor growth and metastasis and is associated with poor prognosis in lung cancer. 81 Moreover, hypomethylation in tumors may trigger genomic instability by reactivating retrotransposon elements or inducing chromosome rearrangements. For example, hypomethylation at the 3′tandem repeat region of the HRAS gene in lung cancer could lead to gene loss. 82 An increase in the hypomethylation of retrotransposable elements (LINE‐1 and Alu) is strongly linked with enhanced transcription and increased genomic instability in lung cancer. 83 This is supported by findings that show a correlation between increased global hypomethylation and higher rates of mutation, copy number variations, and allelic imbalances, as well as shifts in the Treg/CD8 ratio during lung cancer progression (as summarized in Table 1 ).

These insights highlight the multifaceted role of DNA hypomethylation in fostering chromosomal instability, driving mutagenesis, and altering the TME. Although global hypomethylation is often seen in tumor cells, it can also correlate with compact, relatively inactive genomic regions. 84 This reorganization can trigger antitumor immune responses and suppress genes involved in stemness, invasion, and metastasis across various cancers, suggesting that the prevalent global hypomethylation in tumors might result from cumulative cell divisions, potentially playing a tumor‐suppressive role rather than an oncogenic one.

Hypermethylation

While research on hypomethylation is not as extensive, there is a wealth of studies focusing on how hypermethylation affects lung cancers. The inconsistencies in research findings often arise from differences in study designs, types of samples used (like primary tumors versus cell lines), the various histological types of lung cancer, and the methods employed (ranging from quantitative to qualitative analyses, varying numbers of CpG sites studied, different microarray technologies, and diverse statistical approaches). 85 Notably, many potential tumor suppressor genes have been found to be consistently hypermethylated in lung cancers. 86 , 87 , 88 These genes are pivotal in managing key cellular functions that frequently become disrupted in cancer, such as apoptosis (involving genes like CASP8 and DAPK), 89 , 90 , 91 , 92 cell cycle control (e.g., CDKN2A/p16 and PTEN), 38 , 93 , 94 , 95 , 96 , 97 , 98 DNA repair (MGMT, MLH1), 99 , 100 and pathways regulating signaling and cell adhesion (like APC and CDH1). 101 , 102 , 103 , 104 , 105 , 106 , 107 Treatment with methylation inhibitors such as 5‐aza‐2′ deoxycytidine in lung cancer cell lines has been shown to reactivate many of these suppressed genes, 108 confirming their regulation through DNA methylation. Though methylation typically leads to gene silencing, it has also proven useful for identifying epigenetic markers in lung cancer. 109

Intriguingly, some genes exhibit both hypermethylation and hypomethylation, suggesting a sophisticated regulatory mechanism that affects gene expression in complex ways. For example, the UNC5D gene shows hypermethylation at its promoter and hypomethylation in downstream introns in lung cancer. 110 Moreover, hypermethylation doesn't always suppress genes; it can activate them. A notable instance is the hypermethylation of the TERT promoter, which has been found to increase TERT expression in most tumor types, including lung cancers. 104 While similar disruptions by hypermethylation have been observed in other cancers, their effects in lung cancers are still being explored 111 (as summarized in Table 1 ).

These findings emphasize the need to understand the specific epigenetic changes linked to different lung cancer subtypes, smoking status, and genetic alterations. Such detailed knowledge could help uncover distinct mechanisms, assist in the development of targeted diagnostic and prognostic markers, and guide personalized treatment strategies.

DNA methylation studies are important in the detection and treatment of lung cancer. These studies focus on the potential of methylation as a molecular marker and its application in early cancer detection, chemoprevention, diagnosis, treatment or prognosis. Methylation changes usually occur at CGIs in the promoter regions of genes, which makes them ideal biomarkers that can be easily detected by methods such as PCR. In addition, by analyzing the DNA methylation status of a large number of loci, it helps to identify molecular differences between tumors and normal tissues, as well as between different tumor subtypes. This information is expected to be used for the discovery of new markers to improve the detection and diagnoses plan of early‐stage lung cancer. 158

Histone modification

Histone modifications play a pivotal role in the onset and progression of lung cancer, significantly influencing tumor cell function through the fine‐tuning of chromatin structure and gene expression. These modifications, including but not limited to acetylation, methylation, and phosphorylation, alter the interaction between histones and DNA, thereby regulating gene accessibility and expression (Figure 3 ).

Mechanisms of histone modification include methylation, where lysine residues of histones can be methylated to form different methylation states. 159 , 160 This affects chromatin structure and gene accessibility. 161 Phosphorylation, that is, phosphorylation modifications can regulate the interaction of histones with other proteins and affect gene expression. 162 Ubiquitination, that is, ubiquitination modifications are involved in protein degradation and signaling. It also includes crotonylation, glycosylation, and ADP‐ribosylation. Histone modification imbalance is closely related to tumorigenesis and development. 163 In particular, the methylation and acetylation status of histone H3 and H4 residues have been shown to be markers of tumor cells. Acetylation, that is, acetylation modifications are usually associated with gene activation, relaxing chromatin and promoting gene transcription. 164 Acetylation modifications open chromatin structures, making it easier for transcription factors to bind to promoter regions, thereby promoting gene expression. This mechanism leads to the sustained activation of the Wnt pathway in lung cancer cells, which in turn promotes tumor proliferation and aggressiveness. 165 Histone acetylation is often associated with gene activation; when histones around positive regulatory genes in the Wnt signaling pathway (such as those encoding β‐catenin by CTNNB1) undergo acetylation, the transcriptional activity of these genes increases, leading to the activation of the Wnt pathway. Histone deacetylation usually results in gene silencing; reduced transcriptional activity of Wnt pathway inhibitory genes, such as those in the DKK and SFRP families, may be due to histone deacetylation, which can lead to decreased expression of these inhibitors, thereby lifting the inhibition on the Wnt pathway. 166 At the same time, histone deacetylases (HDACs) play a key role in this process. HDAC inhibitors like Vorinostat, by blocking deacetylation, may reactivate these inhibitory genes and counteract the abnormal activation of the Wnt signa. 167 Methylation also plays a role in histone modification; if H3K9 methylation occurs in the promoter regions of Wnt pathway inhibitory genes, these genes may be silenced, leading to the overactivation of the Wnt signaling pathway. Conversely, increased H3K4 methylation may promote the expression of Wnt pathway activation genes, further driving the progression of lung cancer. 168 Due to the importance of histone modifications in regulating the Wnt signaling pathway, drugs targeting histone modifying enzymes including HDACs, HATs, and HMTs are considered to have potential therapeutic value. For example, HDAC inhibitors can partially reverse the abnormal activation of the Wnt signaling pathway by restoring the expression of Wnt inhibitory factors, thereby inhibiting the progression of lung cancer. 169

In lung cancer, aberrant patterns of histone modifications can lead to the downregulation of key tumor suppressor genes or the overexpression of oncogenes, thus promoting tumor growth and dissemination. Specific abnormalities in histone modification, such as the trimethylation of histone H3 on lysine 27 (H3K27me3), have been identified to increase in numerous cases of lung cancer. This modification suppresses the expression of a cohort of tumor suppressor genes, facilitating the proliferation and invasion of lung cancer cells. Moreover, histone modifications affect not only the expression of individual genes but also entire gene expression networks and signaling pathways, including cell cycle regulation, DNA repair, apoptosis, and intercellular signaling, further driving the advancement of lung cancer. YEATS2, a YEATS domain‐containing protein, has been increasingly recognized for its critical role in the pathogenesis of lung cancer. 170 Research has shown that YEATS2 is highly amplified in human lung cancer and is essential for cancer cell growth and survival. 171 The protein binds to acetylated histone H3 through its YEATS domain, influencing gene expression and chromatin structure in cancer cells. This interaction significantly alters the transcriptional program, which is essential for lung cancer tumorigenesis.YEATS2 is not only amplified in lung cancer but also required for the growth and survival of cancer cells. 172 , 173 The research highlighted that the YEATS2‐containing ATAC complex colocalizes with H3K27 acetylation on the promoters of actively transcribed genes. 174 The depletion of YEATS2 or disruption of its interaction with acetylated histones reduces promoter H3K9ac levels and deactivates the expression of essential genes, underlying its pivotal role in lung cancer tumorigenesis (YEATS2 links histone acetylation to tumorigenesis of NSCLC).Furthermore, the role of YEATS2 in various tumors, overexpression of YEATS2 promotes the proliferation and migration of pancreatic cancer cells, and it has been associated with the progression of lung cancer through histone acetylation. YEATS2 also can act as a target of HIF1α and regulate the TAK1/NF‐κB pathway to promote tumor progression in pancreatic cancer, highlighting its potential as a therapeutic target in various cancer types including lung cancer (YEATS2 is a target of HIF1α and promotes pancreatic cancer cell proliferation and migration).These findings underscore the significance of YEATS2 in the molecular pathology of lung cancer, suggesting its potential as a target for therapeutic intervention in cancer treatment.

Messenger RNA modification

The expression patterns and regulatory mechanisms of mRNA play a pivotal role in tumor biology, impacting not only the functionality of genes but also profoundly influencing the pathogenesis of tumors. The regulation of mRNA is particularly critical across many essential signaling pathways, especially concerning tumor progression and the development of treatment resistance. For instance, in the Wnt/β‐catenin pathway, a direct correlation exists between the abnormal activation in lung cancer and the expression levels of β‐catenin mRNA. 175 , 176 In many early‐stage lung cancer specimens, a significant overexpression of β‐catenin mRNA has been observed. 177 , 178 This upregulation not only triggers continuous activation of the Wnt signaling pathway but also propels the cell cycle forward, enhancing cellular proliferation while inhibiting apoptosis, collectively fostering tumor growth and metastasis. 179 , 180

Moreover, the PI3K/Akt/mTOR signaling pathway serves as a critical regulatory axis in tumor development. 181 , 182 Within this pathway, the regulation of Akt mRNA levels is crucial for the progression of lung cancer. Aberrant expression of Akt mRNA often leads to excessive activation of Akt protein, enhancing tumor cell survival and proliferation capabilities and potentially increasing resistance to various therapeutic approaches. 183 , 184 Consequently, the expression and functional status of Akt mRNA and protein have become significant targets in lung cancer treatment. In modern oncology, the detection and analysis of mRNA expression are instrumental in identifying tumor biomarkers. 185 , 186

In addition to coding RNAs, the role of ncRNAs (such as miRNAs and lncRNAs) in lung cancer is increasingly being elucidated. Recent advances in therapeutics based on miRNA and lncRNA are actively being pursued. These strategies, by targeting and modulating specific ncRNAs, can precisely regulate their roles in critical signaling pathways of lung cancer, thus offering new therapeutic options. 187 For instance, by restoring or inhibiting specific miRNAs, it is possible to adjust tumor cell behaviors, affecting their proliferation, migration, or apoptosis, providing more precise molecular targeting for the treatment of early‐stage lung cancer. These studies not only enrich our understanding of the molecular mechanisms of lung cancer but also open new avenues and strategies for future cancer therapies.

ncRNA regulation

In the human genome, genes with the function of coding proteins account for only 2% of all genomic sequences, and the majority of the remaining 98% of the sequences are transcribed into ncRNAs, which are not translated into proteins. These ncRNAs can be categorized into short‐stranded ncRNAs and lncRNAs according to their molecular sizes, and play an important role in epigenetic regulation. 188 They impact cellular proliferation, migration, invasion, and apoptosis through multiple pathways, significantly regulating tumor behavior and its microenvironment. Taking the Wnt/β‐catenin pathway as an example, miR‐34a serves as a key regulatory factor. 189 It inhibits the activation of the Wnt pathway by directly targeting and degrading β‐catenin mRNA, thereby affecting the proliferation and migration of lung cancer cells. Studies have shown that miR‐34a expression is usually downregulated in lung cancer tissues, where it supports the proliferation and survival of lung cancer cells by inhibiting the Wnt pathway. 190 Similarly, the expression of lncRNA HOTAIR is significantly increased in lung cancer, and it can promote the transcriptional activity of β‐catenin by binding to various proteins related to the Wnt signaling pathway, such as EZH2, enhancing the oncogenic effects of the Wnt pathway. 191 In the PI3K/Akt/mTOR pathway, lncRNA GAS5 regulates apoptosis and survival of lung cancer cells by indirectly affecting the phosphorylation status of Akt through inhibiting the expression of mTOR. 192 GAS5, acting as a tumor suppressor gene, is expressed at reduced levels in many lung cancer patients and is negatively correlated with patient prognosis. 193

In terms of drug development, research into ncRNAs has shown potential therapeutic prospects. For instance, miRNA‐based therapeutic strategies, such as the development of synthetic miRNA mimetics or anti‐miRNA oligonucleotides, are currently under development to restore or inhibit the function of specific ncRNAs, regulating key pathways in lung cancer. 194 , 195 These therapies have demonstrated potential in preclinical studies and early clinical trials, especially for patients exhibiting specific ncRNA expression abnormalities (Figure 4 ).

Long noncoding RNAs

While lncRNAs are a type of ncRNA that do not translate into proteins, they significantly influence cellular functions. In the context of lung cancer, lncRNAs are a focal point of research, alongside miRNAs and circRNAs. lncRNAs modulate gene expression through various routes such as interacting with other RNA molecules or proteins, participating in epigenetic modifications, and affecting the structure of chromatin and gene activation. 208 Specific lncRNAs in lung cancer act as either tumor suppressors or oncogenes. For instance, the lncRNA MALAT1 (Metastasis‐Associated Lung Adenocarcinoma Transcript 1) is often upregulated in lung cancer, where it promotes tumor growth and metastasis by influencing cell cycle genes. 209 TUG1 (Taurine Upregulated Gene 1) expression abnormalities are associated with enhanced tumor cell proliferation, migration, and invasion in multiple cancers. 210 Exploring lncRNA regulatory mechanisms is key to understanding lung cancer pathogenesis and progression, pointing to novel therapeutic approaches

Circular RNAs

circRNAs, unique in their covalently closed loop structures, do not encode proteins but are implicated in the molecular etiology of lung cancer. Their role predominantly involves acting as competitive endogenous RNAs or “miRNA sponges,” indirectly modulating gene expression and influencing oncogenic or tumor‐suppressive signaling cascades. 211 Take ciRS‐7, a circRNA that acts as a sponge for miR‐7, altering the expression of several oncogenes and contributing to the molecular mechanisms underlying tumorigenesis. By sequestering miR‐7, ciRS‐7 upregulates target genes like EGFR, which are central to tumor development and progression. 212 Another circRNA, CDR1as, intervenes in the regulation of lung cancer tumor suppressor factors by binding to miR‐7, thereby affecting cellular proliferation and apoptosis. The dysregulation of circRNAs, whether through aberrant expression or modification, plays a critical role in various cancer biology facets, including tumor growth, metastasis, and chemoresistance. Delving into the regulatory machinations of circRNAs unlocks potential for diagnostic and therapeutic innovations in lung cancer. 213

MicroRNAs

miRNAs are small, ncRNA molecules approximately 22 nucleotides in length that play a crucial role in regulating gene expression posttranscriptionally. In lung cancer, miRNAs have emerged as significant biomarkers and therapeutic targets due to their ability to modulate key cancer‐related pathways. 214 miRNAs regulate gene expression by binding to complementary sequences on the 3′ untranslated regions (3′ UTR) of target mRNAs, leading to mRNA degradation or translational repression. This regulation impacts various cellular processes, including cell proliferation, apoptosis, and metastasis. In lung cancer, specific miRNAs can function as oncogenes, known as “oncomiRs,” or as tumor suppressors. 215 For example, miR‐21 is one of the most commonly upregulated miRNAs in lung cancer, acting as an oncomiR by targeting tumor suppressor genes such as PTEN and PDCD4, thereby promoting cancer progression and metastasis. Conversely, let‐7 is a well‐known tumor‐suppressive miRNA in lung cancer, which targets oncogenes like RAS and HMGA2, resulting in the inhibition of tumor growth and spread. The dysregulation of miRNA expression is directly related to the pathogenesis of lung cancer. For instance, miR‐34a, which is downregulated in various types of lung cancer, is known to affect the cell cycle and apoptosis by modulating multiple signaling pathways, such as p53. 216 Additionally, the upregulation of miR‐155 is common in lung cancer, where it promotes tumorigenesis and progression by affecting immune responses and inflammatory processes 217 (as summarized in Table 2 ).

Studying miRNAs in lung cancer helps in understanding the molecular mechanisms of lung carcinogenesis and provides a foundation for developing new diagnostic and therapeutic strategies. miRNAs play a significant role in the pathogenesis and progression of lung cancer. 218 These small, ncRNA molecules are key regulators of gene expression and are involved in various cellular processes, including cell proliferation, differentiation, and apoptosis. 219 In lung cancer, specific miRNAs have been found to be either upregulated or downregulated, making them potential biomarkers for early diagnosis, prognosis, and therapeutic targets. 220

miR‐942 and miR‐601 are examples of miRNAs that are significantly increased in the serum of lung cancer patients. 221 Their elevated levels compared with benign lung diseases and healthy individuals suggest a strong association with lung cancer. These miRNAs could serve as promising molecular signatures for the early detection and prognosis prediction of the disease.

Conversely, miR‐492 and miR‐590‐3p are also identified as differentially expressed in lung cancer. 207 The expression patterns of these miRNAs, along with miR‐631, are distinct enough to differentiate healthy individuals from early‐stage lung cancer patients. This indicates their potential utility as serum biomarkers for the early diagnosis of lung cancer. Biomarkers for Early Diagnosis of Non‐small Cell Lung Cancer. In addition to these, miR‐31 has been studied for its broader role in various pathologies, including lung cancer. This miRNA is differentially expressed in rejecting heart allografts and in serum, and it shows a strong correlation with tissue expression. Such characteristics point to miR‐31's potential as a noninvasive biomarker. Notably, miR‐21 is often found to be overexpressed in lung cancer and is linked to the advancement of the tumor and poorer outcomes. Its engagement in a variety of molecular pathways points to its crucial importance in understanding the development of lung cancer and in crafting novel approaches for early‐stage treatment. 222 , 223 Conversely, miR‐34a typically exhibits reduced expression in lung cancer and acts as a tumor suppressor. 224 Its significant influence on cell cycle control and apoptosis positions it as a promising target for therapeutic intervention. 225

In sum, the study of miRNAs in lung cancer provides invaluable insights into the molecular dynamics of cancer. The capacity to identify and monitor these miRNAs in blood serum could pave the way for noninvasive methods for the early detection, diagnosis, and treatment of lung cancer.

EPIGENETIC REGULATION IN TME

In the lung cancer TME, epigenetic modifications play a critical regulatory role, impacting not only the characteristics of tumor cells themselves but also profoundly influencing the functionality and interactions of various cellular components within the TME, 226 including immune cells, angiogenesis, and stromal cells. Epigenetic changes such as DNA methylation and histone modifications can regulate the expression of tumor cell surface antigens and immune regulatory molecules, significantly affecting the function of immune cells. 227 Specifically, the upregulation of PD‐L1 (Programmed Death‐Ligand 1) enables tumor cells to inhibit T cell activity, effectively evading immune surveillance. 228 In the TME, the methylation level of the PD‐L1 gene significantly influences its expression, directly impacting the tumor cells’ ability to escape immune detection. Low methylation in the promoter region of the PD‐L1 gene is usually associated with increased expression, enhancing the tumor cells’ ability to suppress T cell activity through binding with PD‐1 on T cells, thereby facilitating immune evasion. Furthermore, tumor cells can enhance PD‐L1 expression by activating signaling pathways such as JAK/STAT, PI3K/AKT, and MAPK in response to inflammatory factors like IFN‐γ or internal genetic alterations within the TME. 229 Additionally, changes in the methylation of cytokine or chemotactic factor genes can affect their secretion, thereby influencing the ability of dendritic cells and macrophages to recognize and destroy tumor cells. This regulatory effect is crucial in immune checkpoint therapies, where the epigenetic status directly affects treatment outcomes (as summarized in Table 3 ).

Regarding angiogenesis, epigenetic mechanisms regulate the expression of key factors such as vascular endothelial growth factor (VEGF), essential for tumor growth and dissemination. 230 In the TME, the upregulation of VEGF is controlled by complex epigenetic mechanisms, including histone acetylation and DNA methylation. Specifically, histone acetylation generally enhances the transcriptional activity of certain genes by reducing the affinity of core histones for DNA, thereby making the transcriptional machinery more accessible to these genes. In the case of the VEGF gene, increased levels of histone acetylation can promote an open state in its promoter region, thereby enhancing VEGF transcriptional activity. Concurrently, DNA methylation typically acts at promoter regions to suppress gene expression. However, low methylation states in the VEGF gene promoter may facilitate its upregulation, especially under hypoxic or inflammatory conditions, which are common in tumor environments. Through these epigenetic regulations, VEGF can respond to changes in the tumor environment, promoting angiogenesis and providing the necessary nutrients and oxygen supply for tumor growth and spread. 231 This understanding of VEGF expression regulation not only reveals how tumors adapt their microenvironment through epigenetic mechanisms but also provides potential targets for antitumor strategies aimed at the VEGF signaling pathway. 232

In addition, epigenetic alterations can shift the phenotype of stromal cells from an antitumor to a protumor state, enhancing the tumor‐supportive behavior of the TME. In the TME of lung cancer, tumor cells are able to induce epigenetic reprogramming of surrounding stromal cells (e.g., fibroblasts) through the secretion of specific signaling molecules such as transforming growth factor‐β (TGF‐β). 233 This reprogramming mainly involves alterations in DNA methylation and histone modifications, which affects the gene expression pattern of stromal cells. The signaling pathway activated by TGF‐β promotes the expression of MMPs genes in fibroblasts. 234 These MMPs play an important role in the TME by not only remodeling the surrounding extracellular matrix to provide a physical pathway for tumor invasion, but also by degrading stromal components to promote tumor cell migration and spread. This epigenetic alteration and signaling pathway activation induced by tumor cells suggests that tumors are able to regulate their microenvironment to support their growth and invasion through complex intercellular communication and epigenetic mechanisms. 235 An in‐depth understanding of this mechanism provides important information for the development of therapeutic strategies that target the TME.

In the TME, exosomes play a crucial role, especially in the communication process between tumor cells and surrounding cells. Exosomes can carry and deliver a variety of biomolecules, including miRNAs and mRNAs, which directly affect the epigenetic state and biological behavior of the recipient cells. 236 For example, the delivery of specific miRNAs by tumor cells via exosomes can inhibit the expression of antitumor genes in the recipient cells or activate signaling pathways that promote tumor growth and invasion. 237 This exosome‐mediated signaling not only adjusts the microenvironment around the tumor, but also creates conditions for tumor spread by altering the epigenetic landscape of distant normal or precancerous tissues. Exosomes also have a key role in immune regulation, especially in the tumor immune escape mechanism. Signaling molecules delivered by tumor cells through exosomes can directly affect the activation and function of immune cells, for example, by delivering inhibitory miRNAs or proteins to inhibit the activation and proliferation of T cells or to enhance the inhibitory function of regulatory T cells, which reduces the ability of the immune system to attack tumor cells. 238 In addition, exosomes released by tumor cells can carry immune checkpoint proteins such as PD‐L1, which directly bind to PD‐1 on the surface of T cells and inhibit their activity, further promoting immune escape of tumor cells.

The use of epigenetic mechanisms to modulate immune cells to enhance the efficacy of immunotherapy in the lung cancer TME is a cutting‐edge strategy. By adjusting the methylation and acetylation levels of specific immune‐related genes (e.g., activation and effector molecules of T cells), it is possible to directly affect the expression of these genes, thereby altering the activity and function of immune cells. For example, the antitumor response capacity of T cells can be enhanced by decreasing the methylation level of inhibitory cytokine genes or increasing the acetylation of genes associated with promoting cell activation. In addition, epigenetic modulation targeting immune cells can not only improve their recognition and killing efficiency against tumor cells, but also reduce their depletion status, thereby improving the overall efficacy of existing immunotherapies such as immune checkpoint inhibitors. The implementation of such strategies requires comprehensive consideration of the complex interactions in the TME, as well as the need for individualized medicine to provide patients with more precise and effective treatment options.

CLINICAL APPLICATIONS AND CHALLENGES OF EPIGENETIC BIOMARKERS

In the realm of oncology, epigenetic biomarkers, encompassing DNA methylation, histone modifications, mRNA expression, and exosomal contents, have shown significant promise for enhancing cancer diagnosis, prognosis, and therapeutic strategies. Currently, numerous drugs targeting epigenetic modification markers have been developed for clinical use (as summarized in Table 4 ). However, DNA methylation remains most closely associated with liquid biopsy. 248 DNA methylation patterns serve as early detection markers in liquid biopsies, allowing for the identification of cancer through noninvasive means. Furthermore, the methylation status of tumor suppressor genes offers prognostic value, correlating with disease severity and patient survival outcomes. 249 Histone modifications provide insights into cancer subtypes and progression, facilitating personalized treatment approaches, while specific enzymes responsible for these modifications, such as HDACs and HATs, have emerged as potential therapeutic targets. 250 mRNA levels reflect tumor cell activity and can be used to monitor disease progression and response to treatment. Exosomes play a crucial role as carriers of a diverse array of biomolecules, including DNA, RNA, and proteins, offering a window into the tumor's molecular state through easily accessible body fluids, thus aiding in the tracking of cancer progression or therapeutic response.

The integration of DNA methylation analysis with liquid biopsy technology marks a transformative approach in the realm of oncology, providing a robust method for early cancer detection and continuous monitoring. DNA methylation, which entails the addition of a methyl group primarily to CpG dinucleotides in DNA, alters gene expression without changing the DNA sequence itself. This epigenetic modification, especially the hypermethylation of tumor suppressor genes, can contribute to oncogenesis by silencing critical genes. Liquid biopsy capitalizes on this by detecting ctDNA in body fluids like blood, which retains the genetic and epigenetic characteristics of the original tumor, including methylation patterns. 251 This noninvasive technique allows for the early detection of cancer through simple blood samples, potentially before the tumor is clinically evident or detectable through conventional imaging.

Furthermore, DNA methylation markers in ctDNA offer enhanced specificity and sensitivity in cancer screening, significantly improving early detection and the ability to monitor disease progression or response to treatment. 252 For instance, the methylation status of genes such as SEPT9 in colorectal cancer screening has demonstrated higher sensitivity than traditional fecal occult blood tests. 253 Early detection through these markers has been shown to improve survival rates, as evidenced by studies in cancers such as pancreatic, ovarian, and lung cancer. Additionally, changes in methylation patterns during therapy can provide real‐time insights into treatment efficacy and disease status, aiding in personalized treatment adjustments and improving overall management of the disease. These advances highlight the critical role of epigenetic biomarkers in enhancing diagnostic accuracy, monitoring treatment response, and ultimately improving outcomes for cancer patients.

Despite the significant potential of epigenetic biomarkers, their clinical application faces several challenges. Currently, there is a lack of standardized methods for the extraction and analysis of these biomarkers, particularly exosomes and histone modifications, which impacts the consistency and reproducibility of the data. The sensitivity and specificity of biomarkers can vary greatly among different cancers and their subtypes, making it challenging to identify biomarkers that are both sensitive and specific. 254 Interpreting epigenetic data require specialized knowledge, and translating these findings into clinical practice necessitates further validation and clinical trials. Additionally, ethical and privacy concerns related to the collection and use of patients' genetic and epigenetic information require stringent regulations and guidelines to ensure data protection and ethical compliance. 255 Moreover, epigenetic inhibitors may have adverse effects on the TME. The TME is not uniformly affected by single epigenetic inhibitors. For instance, inhibitors like HDAC inhibitors may have varying effects on different immune cells. ACY‐1215 targets HDAC6 (a class IIb HDAC) while preserving HDAC9 activity, which promotes positive regulation of antitumor immunity. Thus, more in‐depth epigenetic research is needed to clarify the regulatory mechanisms induced by various epigenetic modifications, thereby developing highly selective epigenetic inhibitors for more effective targeting.

CONCLUSIONS AND OUTLOOK

In the context of early‐stage lung cancer, a variety of epigenetic mechanisms play crucial roles in tumor progression. These mechanisms include DNA methylation, histone modifications, the TME, mRNA dynamics, and ncRNAs such as miRNAs, circRNAs, and lncRNAs.

DNA methylation plays a crucial role in suppressing gene activity and maintaining genomic stability by inhibiting recombination events between repetitive sequences. This epigenetic modification often results in the silencing of inhibitory factors or the increased expression of activating factors, which is a common mechanism for the abnormal activation of the Wnt pathway. For example, methylation of the promoter regions of genes such as those in the DKK family (e.g., DKK1, DKK3), the SFRP family (e.g., SFRP1, SFRP2), and WIF1 (Wnt Inhibitory Factor 1) leads to their downregulation or silencing, thereby lifting the inhibition on the Wnt pathway and promoting tumor cell proliferation and survival. 260 In some cases, the positive regulators in the Wnt signaling pathway may be activated due to hypomethylation or other mechanisms, increasing the expression and activity of β‐catenin, which sustains the activation of the Wnt signaling pathway, further promoting the proliferation, invasion, and metastasis of tumor cells. Given the regulatory impact of DNA methylation on the Wnt signaling pathway, drugs targeting DNA methylation, such as DNMT inhibitors (e.g., Azacitidine and Decitabine), 261 may be effective in inhibiting tumor progression. Research is also exploring how to reverse these methylation changes to restore normal regulation of the Wnt signaling pathway.

Histone modifications represent another significant aspect of epigenetic regulation, affecting cancer gene expression through mechanisms such as acetylation and deacetylation, which alter chromatin structure and thereby influence DNA accessibility and transcriptional activity. Acetylation modifications, by opening up chromatin structure, facilitate the binding of transcription factors to promoter regions, thus promoting gene expression. This mechanism leads to the sustained activation of the Wnt pathway in lung cancer cells, thereby promoting tumor proliferation and aggressiveness. Histone acetylation is typically associated with the activation of gene expression, such as the transcriptional activity of β‐catenin encoded by CTNNB1, a key component of the Wnt pathway. 262 Conversely, histone deacetylation usually results in gene silencing, potentially lowering the transcriptional activity of Wnt pathway inhibitory genes, such as those in the DKK and SFRP families, thus lifting the inhibition on the Wnt pathway. At the same time, HDACs play a crucial role in this process; HDAC inhibitors like Vorinostat, by blocking deacetylation, may reactivate these inhibitory genes, thereby countering the abnormal activation of the Wnt signal. 263 Methylation also plays a role in histone modifications; for example, if H3K9 methylation occurs in the promoter regions of Wnt pathway inhibitory genes, it may lead to gene silencing, resulting in the overactivation of the Wnt signaling pathway. Conversely, an increase in H3K4 methylation may promote the expression of genes that activate the Wnt pathway, further driving the progression of lung cancer. 264 Due to the significance of histone modifications in regulating the Wnt signaling pathway, drugs targeting histone‐modifying enzymes, including HDACs, HATs, and HMTs, are considered to have potential therapeutic value. For example, HDAC inhibitors can partially reverse the abnormal activation of the Wnt signaling pathway by restoring the expression of Wnt inhibitory factors, thereby inhibiting the progression of lung cancer.

ncRNAs play a critical regulatory role by finely tuning the expression and activity of specific factors within key signaling pathways. These ncRNAs, including miRNAs, lncRNAs, and circRNAs, significantly regulate tumor behavior and its microenvironment by simultaneously affecting cellular processes such as proliferation, migration, invasion, and apoptosis. Taking the Wnt/β‐catenin pathway as an example, miR‐34a is a key regulator that inhibits the activation of the Wnt pathway by directly targeting and degrading β‐catenin mRNA, thereby affecting the proliferation and migration of lung cancer cells. 265 Research shows that miR‐34a is typically downregulated in lung cancer tissues, and by inhibiting the Wnt pathway, it supports the proliferation and survival of lung cancer cells. Similarly, the expression of lncRNA HOTAIR is significantly increased in lung cancer, and it can promote the transcriptional activity of β‐catenin by binding to various proteins associated with the Wnt signaling pathway, such as EZH2, thereby enhancing the oncogenic effects of the Wnt pathway. 266 In the PI3K/Akt/mTOR pathway, lncRNA GAS5 regulates the apoptosis and survival of lung cancer cells by indirectly affecting the phosphorylation state of Akt through inhibiting the expression of mTOR. 267 GAS5 acts as a tumor suppressor gene, and its expression is reduced in many lung cancer patients, negatively correlating with patient prognosis. In terms of drug development, research into ncRNAs has shown potential therapeutic prospects. 268 For example, miRNA‐based therapeutic strategies, such as the development of synthetic miRNA mimetics or anti‐miRNA oligonucleotides, are currently being developed to restore or inhibit the function of specific ncRNAs, regulating key pathways in lung cancer. These therapies have shown potential in preclinical studies and early clinical trials, especially for patients with specific ncRNA expression abnormalities.

In the field of early‐stage lung cancer diagnostics, the combination of liquid biopsy techniques and the detection of epigenetic modification markers has significantly enhanced the accuracy and feasibility of early detection. Liquid biopsy is a noninvasive approach that analyzes ctDNA, cell‐free DNA, and other biomarkers in blood to detect cancer potentially up to 4 years before abnormalities are visible through conventional imaging studies. Specifically, epigenetic alterations, such as DNA methylation, precede common genetic mutations in the development of lung cancer. Research on the methylation of the SHOX2 gene indicates a significant elevation in the methylation levels among lung cancer patients, which can be detected through blood samples and thus serve as an early diagnostic marker for asymptomatic high‐risk populations. Moreover, the analysis of methylation profiles in patient blood has successfully identified lung cancer in advance, demonstrating the potential of liquid biopsy techniques in preclinical studies. The use of composite epigenetic biomarkers, including specific patterns of DNA methylation and histone modifications, effectively distinguishes between healthy individuals and lung cancer patients. These instances illustrate that integrating liquid biopsy with the detection of epigenetic modifications not only offers an efficient strategy for the early diagnosis of lung cancer but also aids in understanding the pathogenesis of the disease and in developing new treatment approaches. However, epigenetic modulators may adversely affect the TME. Despite the development of numerous drugs targeting epigenetic factors, epigenetic inhibitors could potentially have detrimental impacts on the TME, as TME is not uniformly affected by a single epigenetic inhibitor. For instance, HDAC inhibitors might differentially impact various immune cells. ACY‐1215 targets HDAC6 (Class IIb HDAC) while preserving HDAC9 activity, promoting positive regulation of antitumor immunity. Importantly, the mechanisms of action of epigenetic regulatory factors are complex; in cancer, they may need to maintain the expression of some key target genes. If these regulators are broadly targeted, the balance could be disrupted enough to lead to cellular catastrophe. Therefore, further in‐depth epigenetic research is necessary to delineate the characteristics of various epigenetic modifications in tumor regulation, thereby developing highly selective epigenetic inhibitors for more effective targeting efficiency.

AUTHOR CONTRIBUTIONS

Writing—original draft; conceptualization; visualization : Lingfeng Bi. Supervision : Xin Wang and Jiayi Li. Writing—review and editing; project administration; supervision; funding acquisition : Zhoufeng Wang. Writing—review and editing; project administration; supervision; funding acquisition : Weimin Li. All authors have read and approved the article.

CONFLICT OF INTEREST STATMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

Not applicable.

ACKNOWLEDGMENTS

This work was supported by National Natural Science Foundation of China (Nos. 32370628, 92159302, 32170592); the Science and Technology Project of Sichuan (Nos. 2022ZDZX0018, 2023NSFSC004), and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYGD22009).

DATA AVAILABILITY STATEMENT

Not applicable.

REFERENCES

1 Zheng RS , Chen R , Han BF , et al. [Cancer incidence and mortality in China, 2022] . Zhonghua Zhong Liu Za Zhi . 2024 ; 46 ( 3 ): 221 ‐ 231 . 38468501 10.3760/cma.j.cn112152-20240119-00035

2 Qiu X , Zhang H , Zhao Y , et al. Application of circulating genetically abnormal cells in the diagnosis of early‐stage lung cancer . J Cancer Res Clin Oncol . 2022 ; 148 ( 3 ): 685 ‐ 695 . 33893839 10.1007/s00432-021-03648-w PMC11801133

3 Quaranta V , Linkous A . Organoids as a systems platform for SCLC brain metastasis . Front Oncol . 2022 ; 12 : 881989 . 35574308 10.3389/fonc.2022.881989 PMC9096159

4 Gridelli C , Rossi A , Carbone DP , et al. Non‐small‐cell lung cancer . Nat Rev Dis Primers . 2015 ; 1 : 15009 . 27188576 10.1038/nrdp.2015.9

5 Qian C , Zou X , Li W , Li Y , Yu W . The outpost against cancer: universal cancer only markers . Cancer Biol Med . 2023 ; 20 ( 11 ): 806 ‐ 815 . 38018033 10.20892/j.issn.2095-3941.2023.0313 PMC10690883

6 Pierce SE , Granja JM , Corces MR , et al. LKB1 inactivation modulates chromatin accessibility to drive metastatic progression . Nat Cell Biol . 2021 ; 23 ( 8 ): 915 ‐ 924 . 34341533 10.1038/s41556-021-00728-4 PMC8355205

7 Wang Y , Douville C , Cohen JD , et al. Detection of rare mutations, copy number alterations, and methylation in the same template DNA molecules . Proc Nat Acad Sci USA . 2023 ; 120 ( 15 ): e2220704120 . 37014860 10.1073/pnas.2220704120 PMC10104560

8 Lim WH , Lee KH , Lee JH , et al. Diagnostic performance and prognostic value of CT‐defined visceral pleural invasion in early‐stage lung adenocarcinomas . Eur Radiol . 2024 ; 34 ( 3 ): 1934 ‐ 1945 . 37658899 10.1007/s00330-023-10204-2

9 Silvestri GA , Goldman L , Tanner NT , et al. Outcomes from more than 1 million people screened for lung cancer with low‐dose CT imaging . Chest . 2023 ; 164 ( 1 ): 241 ‐ 251 . 36773935 10.1016/j.chest.2023.02.003 PMC10331628

10 Nagasaka M , Uddin MH , Al‐Hallak MN , et al. Liquid biopsy for therapy monitoring in early‐stage non‐small cell lung cancer . Mol Cancer . 2021 ; 20 ( 1 ): 82 . 34074295 10.1186/s12943-021-01371-1 PMC8170728

11 Li P , Liu S , Du L , Mohseni G , Zhang Y , Wang C . Liquid biopsies based on DNA methylation as biomarkers for the detection and prognosis of lung cancer . Clinical epigenetics . 2022 ; 14 ( 1 ): 118 . 36153611 10.1186/s13148-022-01337-0 PMC9509651

12 Shields MD , Chen K , Dutcher G , Patel I , Pellini B . Making the rounds: exploring the role of circulating tumor DNA (ctDNA) in non‐small cell lung cancer . Int J Mol Sci . 2022 ; 23 ( 16 ): 9006 . 36012272 10.3390/ijms23169006 PMC9408840

13 Wadowska K , Bil‐Lula I , Trembecki Ł , Śliwińska‐Mossoń M . Genetic markers in lung cancer diagnosis: a review . Int J Mol Sci . 2020 ; 21 ( 13 ): 4569 . 32604993 10.3390/ijms21134569 PMC7369725

14 Tomasetti M , Amati M , Neuzil J , Santarelli L . Circulating epigenetic biomarkers in lung malignancies: from early diagnosis to therapy . Lung cancer (Amsterdam, Netherlands)ss . 2017 ; 107 : 65 ‐ 72 . 10.1016/j.lungcan.2016.05.023 27312601

15 Nooreldeen R , Bach H . Current and future development in lung cancer diagnosis . Int J Mol Sci . 2021 ; 22 ( 16 ): 8661 . 34445366 10.3390/ijms22168661 PMC8395394

16 Inamura K . Clinicopathological characteristics and mutations driving development of early lung adenocarcinoma: tumor initiation and progression . Int J Mol Sci . 2018 ; 19 ( 4 ): 1259 . 29690599 10.3390/ijms19041259 PMC5979290

17 Wang B , Shen XY , Pan LY , et al. The HDAC2‐MTA3 interaction induces nonsmall cell lung cancer cell migration and invasion by targeting c‐Myc and cyclin D1 . Mol Carcinog . 2023 ; 62 ( 11 ): 1630 ‐ 1644 . 37401867 10.1002/mc.23604

18 Travis WD , Brambilla E , Noguchi M , et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma . J Thorac Oncol . 2011 ; 6 ( 2 ): 244 ‐ 285 . 21252716 10.1097/JTO.0b013e318206a221 PMC4513953

19 Yotsukura M , Asamura H , Motoi N , et al. Long‐term prognosis of patients with resected adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung . J Thorac Oncol . 2021 ; 16 ( 8 ): 1312 ‐ 1320 . 33915249 10.1016/j.jtho.2021.04.007

20 Tan X , Zhang S , Gao H , et al. Hypermethylation of the PTTG1IP promoter leads to low expression in early‐stage non‐small cell lung cancer . Oncol Lett . 2019 ; 18 ( 2 ): 1278 ‐ 1286 . 31423188 10.3892/ol.2019.10400 PMC6607221

21 Lin J , Zandi R , Shao R , et al. A miR‐SNP biomarker linked to an increased lung cancer survival by miRNA‐mediated down‐regulation of FZD4 expression and Wnt signaling . Sci Rep . 2017 ; 7 ( 1 ): 9029 . 28831115 10.1038/s41598-017-09604-4 PMC5567228

22 Gao Q , Lin YP , Li BS , et al. Unintrusive multi‐cancer detection by circulating cell‐free DNA methylation sequencing (THUNDER): development and independent validation studies . Ann Oncol . 2023 ; 34 ( 5 ): 486 ‐ 495 . 36849097 10.1016/j.annonc.2023.02.010

23 Yang R , Peng W , Shi S , et al. The NLRP11 protein bridges the histone lysine acetyltransferase KAT7 to acetylate vimentin in the early stage of lung adenocarcinoma . Advanced Science (Weinheim, Baden‐Wurttemberg, Germany) . 2023 ; 10 ( 25 ): e2300971 . 37424170 10.1002/advs.202300971 PMC10477884

24 Peng H , Wu X , Zhong R , et al. Profiling tumor immune microenvironment of non‐small cell lung cancer using multiplex immunofluorescence . Front Immunol . 2021 ; 12 : 750046 . 34804034 10.3389/fimmu.2021.750046 PMC8600321

25 Tan Y , Johnson M , Zhou J , Zhao Y , Kamal MA , Qu X . Antrodia cinnamomea inhibits growth and migration of lung cancer cells through regulating p53‐Bcl2 and MMPs pathways . Am J Chin Med . 2020 ; 48 ( 8 ): 1941 ‐ 1953 . 33300478 10.1142/S0192415X20500974

26 Shen KH , Hung JH , Liao YC , Tsai ST , Wu MJ , Chen PS . Sinomenine inhibits migration and invasion of human lung cancer cell through downregulating expression of miR‐21 and MMPs . Int J Mol Sci . 2020 ; 21 ( 9 ): 3080 . 32349289 10.3390/ijms21093080 PMC7247699

27 Chen P , Rojas FR , Hu X , et al. Pathomic features reveal immune and molecular evolution from lung preneoplasia to invasive adenocarcinoma . Mod Pathol . 2023 ; 36 ( 12 ): 100326 . 37678674 10.1016/j.modpat.2023.100326 PMC10841057

28 Malyla V , Paudel KR , De Rubis G , Hansbro NG , Hansbro PM , Dua K . Cigarette smoking induces lung cancer tumorigenesis via upregulation of the WNT/β‐catenin signaling pathway . Life Sci . 2023 ; 326 : 121787 . 37209867 10.1016/j.lfs.2023.121787

29 Bao Y , Zhang S , Zhang X , et al. RBM10 loss promotes EGFR‐driven lung cancer and confers sensitivity to spliceosome inhibition . Cancer Res . 2023 ; 83 ( 9 ): 1490 ‐ 1502 . 36853175 10.1158/0008-5472.CAN-22-1549

30 Savari O , Febres‐Aldana C , Chang JC , et al. Non‐small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours . Histopathology . 2023 ; 82 ( 2 ): 242 ‐ 253 . 36130728 10.1111/his.14801 PMC10501689

31 George J , Lim JS , Jang SJ , et al. Comprehensive genomic profiles of small cell lung cancer . Nature . 2015 ; 524 ( 7563 ): 47 ‐ 53 . 26168399 10.1038/nature14664 PMC4861069

32 Duan J , Zhong B , Fan Z , et al. DNA methylation in pulmonary fibrosis and lung cancer . Expert Rev Respir Med . 2022 ; 16 ( 5 ): 519 ‐ 528 . 35673969 10.1080/17476348.2022.2085091 PMC9276636

33 Ramazi S , Daddzadi M , Sahafnejad Z , Allahverdi A . Epigenetic regulation in lung cancer . MedComm . 2023 ; 4 ( 6 ): e401 . 37901797 10.1002/mco2.401 PMC10600507

34 Xu Q , Wang C , Zhou JX , et al. Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development . Proc Nat Acad Sci USA . 2022 ; 119 ( 6 ): e2107599119 . 35110400 10.1073/pnas.2107599119 PMC8832965

35 Boo HJ , Min HY , Park CS , et al. Dual impact of IGF2 on alveolar stem cell function during tobacco‐induced injury repair and development of pulmonary emphysema and cancer . Cancer Res . 2023 ; 83 ( 11 ): 1782 ‐ 1799 . 36971490 10.1158/0008-5472.CAN-22-3543

36 Ebisudani T , Hamamoto J , Togasaki K , et al. Genotype‐phenotype mapping of a patient‐derived lung cancer organoid biobank identifies NKX2‐1‐defined Wnt dependency in lung adenocarcinoma . Cell Rep . 2023 ; 42 ( 3 ): 112212 . 36870059 10.1016/j.celrep.2023.112212

37 Jin C , Wang T , Zhang D , et al. Acetyltransferase NAT10 regulates the Wnt/β‐catenin signaling pathway to promote colorectal cancer progression via ac(4)C acetylation of KIF23 mRNA . J Exp Clin Cancer Res . 2022 ; 41 ( 1 ): 345 . 36522719 10.1186/s13046-022-02551-7 PMC9753290

38 Satpathy S , Krug K , Jean Beltran PM , et al. A proteogenomic portrait of lung squamous cell carcinoma . Cell . 2021 ; 184 ( 16 ): 4348 ‐ 4371.e4340 . 34358469 10.1016/j.cell.2021.07.016 PMC8475722

39 Sun Y , Sun J , Ying K , et al. EP300 regulates the SLC16A1‐AS1‐AS1/TCF3 axis to promote lung cancer malignancies through the Wnt signaling pathway . Heliyon . 2024 ; 10 ( 6 ): e27727 . 38515708 10.1016/j.heliyon.2024.e27727 PMC10955305

40 Teng PC , Liang Y , Yarmishyn AA , et al. RNA modifications and epigenetics in modulation of lung cancer and pulmonary diseases . Int J Mol Sci . 2021 ; 22 ( 19 ): 10592 . 34638933 10.3390/ijms221910592 PMC8508636

41 Chi Y , Wang D , Wang J , Yu W , Yang J . Long non‐coding RNA in the pathogenesis of cancers . Cells . 2019 ; 8 ( 9 ): 1015 . 31480503 10.3390/cells8091015 PMC6770362

42 Zhao J , Guo C , Ma Z , Liu H , Yang C , Li S . Identification of a novel gene expression signature associated with overall survival in patients with lung adenocarcinoma: A comprehensive analysis based on TCGA and GEO databases . Lung Cancer . 2020 ; 149 : 90 ‐ 96 . 33002836 10.1016/j.lungcan.2020.09.014

43 Miyoshi J , Zhu Z , Luo A , et al. A microRNA‐based liquid biopsy signature for the early detection of esophageal squamous cell carcinoma: a retrospective, prospective and multicenter study . Mol Cancer . 2022 ; 21 ( 1 ): 44 . 35148754 10.1186/s12943-022-01507-x PMC8832722

44 Li W , Liu S , Su S , Chen Y , Sun G . Construction and validation of a novel prognostic signature of microRNAs in lung adenocarcinoma . PeerJ . 2021 ; 9 : e10470 . 33510968 10.7717/peerj.10470 PMC7798616

45 Lee TJ , Yuan X , Kerr K , et al. Strategies to modulate microRNA functions for the treatment of cancer or organ injury . Pharmacol Rev . 2020 ; 72 ( 3 ): 639 ‐ 667 . 32554488 10.1124/pr.119.019026 PMC7300323

46 Yang H , Liu Y , Chen L , et al. MiRNA‐based therapies for lung cancer: opportunities and challenges? Biomolecules . 2023 ; 13 ( 6 ): 877 . 37371458 10.3390/biom13060877 PMC10295928

47 Huang YH , Chiu LY , Tseng JS , et al. Attenuation of PI3K‐Akt‐mTOR pathway to reduce cancer stemness on chemoresistant lung cancer cells by shikonin and synergy with BEZ235 inhibitor . Int J Mol Sci . 2024 ; 25 ( 1 ): 616 . 38203787 10.3390/ijms25010616 PMC10779050

48 Liu M , Hu S , Yan N , Popowski KD , Cheng K . Inhalable extracellular vesicle delivery of IL‐12 mRNA to treat lung cancer and promote systemic immunity . Nat Nanotechnol . 2024 ; 19 ( 4 ): 565 ‐ 575 . 38212521 10.1038/s41565-023-01580-3 PMC12930425

49 Wan G , Liu Y , Zhu J , et al. SLFN5 suppresses cancer cell migration and invasion by inhibiting MT1‐MMP expression via AKT/GSK‐3β/β‐catenin pathway . Cell Signalling . 2019 ; 59 : 1 ‐ 12 . 30844429 10.1016/j.cellsig.2019.03.004

50 Zhang J , Zhang X , Yang S , Bao Y , Xu D , Liu L . FOXH1 promotes lung cancer progression by activating the Wnt/β‐catenin signaling pathway . Cancer Cell Int . 2021 ; 21 ( 1 ): 293 . 34090445 10.1186/s12935-021-01995-9 PMC8180118

51 D'Ambrosi S , Giannoukakos S , Antunes‐Ferreira M , et al. Combinatorial blood platelets‐derived circRNA and mRNA signature for early‐stage lung cancer detection . Int J Mol Sci . 2023 ; 24 ( 5 ): 4881 . 36902312 10.3390/ijms24054881 PMC10003255

52 Liu W , Powell CA , Wang Q . Tumor microenvironment in lung cancer‐derived brain metastasis . Chin Med J (Engl) . 2022 ; 135 ( 15 ): 1781 ‐ 1791 . 35838548 10.1097/CM9.0000000000002127 PMC9521756

53 Hinshaw DC , Shevde LA . The tumor microenvironment innately modulates cancer progression . Cancer Res . 2019 ; 79 ( 18 ): 4557 ‐ 4566 . 31350295 10.1158/0008-5472.CAN-18-3962 PMC6744958

54 Xu K , Zhang C , Du T , et al. Progress of exosomes in the diagnosis and treatment of lung cancer . Biomed Pharmacother . 2021 ; 134 : 111111 . 33352449 10.1016/j.biopha.2020.111111

55 Enfield KSS , Colliver E , Lee C , et al. Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer . Cancer Discov . 2024 ; 14 ( 6 ): 1018 ‐ 1047 . 38581685 10.1158/2159-8290.CD-23-1380 PMC11145179

56 Nikanjam M , Kato S , Kurzrock R . Liquid biopsy: current technology and clinical applications . J Hematol Oncol . 2022 ; 15 ( 1 ): 131 . 36096847 10.1186/s13045-022-01351-y PMC9465933

57 Li W , Liu JB , Hou LK , et al. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring . Mol Cancer . 2022 ; 21 ( 1 ): 25 . 35057806 10.1186/s12943-022-01505-z PMC8772097

58 Baca SC , Seo JH , Davidsohn MP , et al. Liquid biopsy epigenomic profiling for cancer subtyping . Nat Med . 2023 ; 29 ( 11 ): 2737 ‐ 2741 . 37865722 10.1038/s41591-023-02605-z PMC10695830

59 Kubiliute R , Jarmalaite S . Epigenetic biomarkers of renal cell carcinoma for liquid biopsy tests . Int J Mol Sci . 2021 ; 22 ( 16 ): 8846 . 34445557 10.3390/ijms22168846 PMC8396354

60 Heeke S , Gay CM , Estecio MR , et al. Tumor‐ and circulating‐free DNA methylation identifies clinically relevant small cell lung cancer subtypes . Cancer Cell . 2024 ; 42 ( 2 ): 225 ‐ 237.e225 . 38278149 10.1016/j.ccell.2024.01.001 PMC10982990

61 Yu D , Li Y , Wang M , et al. Exosomes as a new frontier of cancer liquid biopsy . Mol Cancer . 2022 ; 21 ( 1 ): 56 . 35180868 10.1186/s12943-022-01509-9 PMC8855550

62 Jiang C , Zhang N , Hu X , Wang H . Tumor‐associated exosomes promote lung cancer metastasis through multiple mechanisms . Mol Cancer . 2021 ; 20 ( 1 ): 117 . 34511114 10.1186/s12943-021-01411-w PMC8436438

63 Khan FH , Reza MJ , Shao YF , et al. Role of exosomes in lung cancer: a comprehensive insight from immunomodulation to theragnostic applications . Biochimica et biophysica acta Reviews on cancer . 2022 ; 1877 ( 5 ): 188776 . 35961620 10.1016/j.bbcan.2022.188776

64 Mattei AL , Bailly N , Meissner A . DNA methylation: a historical perspective . Trends Genet . 2022 ; 38 ( 7 ): 676 ‐ 707 . 35504755 10.1016/j.tig.2022.03.010

65 Horvath S , Raj K . DNA methylation‐based biomarkers and the epigenetic clock theory of ageing . Nat Rev Genet . 2018 ; 19 ( 6 ): 371 ‐ 384 . 29643443 10.1038/s41576-018-0004-3

66 Liang W , Zhao Y , Huang W , et al. Non‐invasive diagnosis of early‐stage lung cancer using high‐throughput targeted DNA methylation sequencing of circulating tumor DNA (ctDNA) . Theranostics . 2019 ; 9 ( 7 ): 2056 ‐ 2070 . 31037156 10.7150/thno.28119 PMC6485294

67 Karlow JA , Pehrsson EC , Xing X , et al. Non‐small cell lung cancer epigenomes exhibit altered DNA methylation in smokers and never‐smokers . Genomics Proteomics Bioinformatics . 2023 ; 21 ( 5 ): 991 ‐ 1013 . 37742993 10.1016/j.gpb.2023.03.006 PMC10928376

68 Liu S , Chen X , Chen R , et al. Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer . Oncotarget . 2017 ; 8 ( 22 ): 36354 ‐ 36367 . 28422739 10.18632/oncotarget.16754 PMC5482660

69 Sarne V , Huter S , Braunmueller S , et al. Promoter methylation of selected genes in non‐small‐cell lung cancer patients and cell lines . Int J Mol Sci . 2020 ; 21 ( 13 ): 4595 . 32605217 10.3390/ijms21134595 PMC7369760

70 Hua F , Fang N , Li X , Zhu S , Zhang W , Gu J . A meta‐analysis of the relationship between RARβ gene promoter methylation and non‐small cell lung cancer . PLoS One . 2014 ; 9 ( 5 ): e96163 . 24796328 10.1371/journal.pone.0096163 PMC4010458

71 Mazieres J , He B , You L , Xu Z , Jablons DM . Wnt signaling in lung cancer . Cancer Lett . 2005 ; 222 ( 1 ): 1 ‐ 10 . 15837535 10.1016/j.canlet.2004.08.040

72 Kim MJ , Min Y , Jeong SK , et al. USP15 negatively regulates lung cancer progression through the TRAF6‐BECN1 signaling axis for autophagy induction . Cell Death Dis . 2022 ; 13 ( 4 ): 348 . 35422093 10.1038/s41419-022-04808-7 PMC9010460

73 Young IC , Brabletz T , Lindley LE , et al. Multi‐cancer analysis reveals universal association of oncogenic LBH expression with DNA hypomethylation and WNT‐Integrin signaling pathways . Cancer Gene Ther . 2023 ; 30 ( 9 ): 1234 ‐ 1248 . 37268816 10.1038/s41417-023-00633-y PMC10501907

74 Wang X , Ju S , Chen Y , et al. Hypomethylation‐activated cancer‐testis gene SPANXC promotes cell metastasis in lung adenocarcinoma . J Cell Mol Med . 2019 ; 23 ( 11 ): 7261 ‐ 7267 . 31483565 10.1111/jcmm.14532 PMC6815806

75 Guo H , Vuille JA , Wittner BS , et al. DNA hypomethylation silences anti‐tumor immune genes in early prostate cancer and CTCs . Cell . 2023 ; 186 ( 13 ): 2765 ‐ 2782.e2728 . 37327786 10.1016/j.cell.2023.05.028 PMC10436379

76 Sun Z , Zhang R , Zhang X , et al. LINE‐1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non‐small cell lung cancer . Mol Cancer . 2022 ; 21 ( 1 ): 147 . 35842613 10.1186/s12943-022-01618-5 PMC9288060

77 Vylegzhanina AV , Bespalov IA , Novototskaya‐Vlasova KA , et al. Cancer relevance of circulating antibodies against LINE‐1 antigens in humans . Cancer research communications . 2023 ; 3 ( 11 ): 2256 ‐ 2267 . 37870410 10.1158/2767-9764.CRC-23-0289 PMC10631453

78 Bacolod MD , Barany F , Fisher PB . Can CpG methylation serve as surrogate markers for immune infiltration in cancer? Adv Cancer Res . 2019 ; 143 : 351 ‐ 384 . 31202362 10.1016/bs.acr.2019.03.007

79 Fei J , Xiao C , Yang M , Zhou X , Gong P . Inhibition of SNCG suppresses the proliferation of lung cancer cells induced by high glucose . Mol Med Rep . 2021 ; 23 ( 2 ): 138 . 33313952 10.3892/mmr.2020.11777 PMC7751455

80 Zhang B , Ren Z , Zhao J , et al. Global analysis of HLA‐A2 restricted MAGE‐A3 tumor antigen epitopes and corresponding TCRs in non‐small cell lung cancer . Theranostics . 2023 ; 13 ( 13 ): 4449 ‐ 4468 . 37649599 10.7150/thno.84710 PMC10465222

81 Zhou D , Zheng H , Liu Q , et al. Attenuated plasmodium sporozoite expressing MAGE‐A3 induces antigen‐specific CD8+ T cell response against lung cancer in mice . Cancer Biol Med . 2019 ; 16 ( 2 ): 288 ‐ 298 . 31516749 10.20892/j.issn.2095-3941.2018.0309 PMC6713645

82 Tang R , Shuldiner EG , Kelly M , et al. Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS‐driven lung cancer growth . Nat Cell Biol . 2023 ; 25 ( 1 ): 159 ‐ 169 . 36635501 10.1038/s41556-022-01049-w PMC10521195

83 Park MK , Lee JC , Lee JW , Hwang SJ . Alu cell‐free DNA concentration, Alu index, and LINE‐1 hypomethylation as a cancer predictor . Clin Biochem . 2021 ; 94 : 67 ‐ 73 . 33901468 10.1016/j.clinbiochem.2021.04.021

84 Liu L , Wang C , Li S , et al. ERO1L is a novel and potential biomarker in lung adenocarcinoma and shapes the immune‐suppressive tumor microenvironment . Front Immunol . 2021 ; 12 : 677169 . 34354701 10.3389/fimmu.2021.677169 PMC8329662

85 Wang J , Zhao Y , Xu H , et al. Silencing NID2 by DNA hypermethylation promotes lung cancer . Pathol Oncol Res . 2020 ; 26 ( 2 ): 801 ‐ 811 . 30826972 10.1007/s12253-019-00609-0

86 Wang Y , Wei J , Feng L , et al. Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR‐mutant non‐small‐cell lung cancer . Mol Cancer . 2023 ; 22 ( 1 ): 81 . 37161388 10.1186/s12943-023-01780-4 PMC10169458

87 Wu J , He K , Zhang Y , et al. Inactivation of SMARCA2 by promoter hypermethylation drives lung cancer development . Gene . 2019 ; 687 : 193 ‐ 199 . 30447346 10.1016/j.gene.2018.11.032

88 Kim JY , Choi JK , Jung H . Genome‐wide methylation patterns predict clinical benefit of immunotherapy in lung cancer . Clin Epigenetics . 2020 ; 12 ( 1 ): 119 . 32762727 10.1186/s13148-020-00907-4 PMC7410160

89 Yoo SS , Choi JE , Lee WK , et al. Polymorphisms in the CASPASE genes and survival in patients with early‐stage non‐small‐cell lung cancer . J Clin Oncol . 2009 ; 27 ( 34 ): 5823 ‐ 5829 . 19826114 10.1200/JCO.2009.23.1738

90 Chen Z , Fan Y , Liu X , Shang X , Qi K , Zhang S . Clinicopathological significance of DAPK gene promoter hypermethylation in non‐small cell lung cancer: A meta‐analysis . Int J Biol Markers . 2022 ; 37 ( 1 ): 47 ‐ 57 . 34935548 10.1177/17246008211067552

91 Kang C , Wang D , Zhang X , Wang L , Wang F , Chen J . Construction and validation of a lung cancer diagnostic model based on 6‐gene methylation frequency in blood, clinical features, and serum tumor markers . Comput Math Methods Med . 2021 ; 2021 : 9987067 . 34257703 10.1155/2021/9987067 PMC8257360

92 Li Y , Fan QX . [ The role of lung cancer related gene methylation in the early diagnosis of lung cancer] . Zhonghua Zhong Liu Za Zhi . 2020 ; 42 ( 8 ): 644 ‐ 647 . 32867455 10.3760/cma.j.cn112152-20190311-00144

93 Porcel JM . Pleural mesothelioma . Med Clin (Barc) . 2022 ; 159 ( 5 ): 240 ‐ 247 . 35636988 10.1016/j.medcli.2022.03.007

94 Li DM , Li GS , Li JD , et al. Clinical significance and prospective mechanism of increased CDKN2A expression in small cell lung cancer . Clin Transl Oncol . 2024 ; 26 ( 6 ): 1519 ‐ 1531 . 38206516 10.1007/s12094-023-03376-2 PMC11108933

95 Reyes NS , Krasilnikov M , Allen NC , et al. Sentinel p16(INK4a+) cells in the basement membrane form a reparative niche in the lung . Science . 2022 ; 378 ( 6616 ): 192 ‐ 201 . 36227993 10.1126/science.abf3326 PMC10621323

96 Mohammed F , Baydaa Abed Hussein A , Ahmed T . Evaluation of methylation panel in the promoter region of p16(INK4a), RASSF1A, and MGMT as a biomarker in sputum for lung cancer . Arch Razi Inst . 2022 ; 77 ( 3 ): 1075 ‐ 1081 . 36618318 10.22092/ARI.2022.357985.2131 PMC9759213

97 Yehia L , Centomo ML , Pandolfi PP , Eng C . Two's company, three's a crowd: Rb1/Trp53/Pten trifecta and lung cancer molecular and histopathologic heterogeneity . J Thorac Oncol . 2023 ; 18 ( 3 ): 260 ‐ 261 . 36842808 10.1016/j.jtho.2022.12.011

98 Li J , Zhou S , Li H , Xu Y , Zhou N , Liu R . PTEN/AKT upregulation of TMSB10 contributes to lung cancer cell growth and predicts poor survival of the patients . Biosci Biotechnol Biochem . 2021 ; 85 ( 4 ): 805 ‐ 813 . 33686397 10.1093/bbb/zbaa113

99 Chen B , Ying X , Bao L . MGMT gene promoter methylation in humoral tissue as biomarker for lung cancer diagnosis: An update meta‐analysis . Thoracic cancer . 2021 ; 12 ( 23 ): 3194 ‐ 3200 . 34651448 10.1111/1759-7714.14186 PMC8636218

100 Tsuboi M , Kondo K , Soejima S , et al. Chromate exposure induces DNA hypermethylation of the mismatch repair gene MLH1 in lung cancer . Mol Carcinog . 2020 ; 59 ( 1 ): 24 ‐ 31 . 31579968 10.1002/mc.23125

101 Emam M , Machado JP , Antunes A . Evolutionary genomics of mammalian lung cancer genes reveals signatures of positive selection in APC, RB1 and TP53 . Genomics . 2020 ; 112 ( 6 ): 4722 ‐ 4731 . 32818633 10.1016/j.ygeno.2020.08.020

102 Liu F , Lu X , Zhou X , Huang H . APC gene promoter methylation as a potential biomarker for lung cancer diagnosis: a meta‐analysis . Thoracic cancer . 2021 ; 12 ( 21 ): 2907 ‐ 2913 . 34545707 10.1111/1759-7714.14151 PMC8563159

103 Ren K , Sun J , Liu L , et al. TP53‐activated lncRNA GHRLOS regulates cell proliferation, invasion, and apoptosis of non‐small cell lung cancer by modulating the miR‐346/APC axis . Front Oncol . 2021 ; 11 : 676202 . 33968785 10.3389/fonc.2021.676202 PMC8097184

104 Paschidis K , Zougros A , Chatziandreou I , et al. Methylation analysis of APC, AXIN2, DACT1, RASSF1A and MGMT gene promoters in non‐small cell lung cancer . Pathol Res Pract . 2022 ; 234 : 153899 . 35489124 10.1016/j.prp.2022.153899

105 Zhao JS , Shi S , Qu HY , et al. Glutamine synthetase licenses APC/C‐mediated mitotic progression to drive cell growth . Nature metabolism . 2022 ; 4 ( 2 ): 239 ‐ 253 . 10.1038/s42255-021-00524-2 35145325

106 Zhang S , You X , Zheng Y , Shen Y , Xiong X , Sun Y . The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells . J Clin Invest . 2023 ; 133 ( 4 ): e162434 . 36548081 10.1172/JCI162434 PMC9927933

107 Dong Y , Hu H , Zhang X , et al. Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis . Signal transduction and targeted therapy . 2023 ; 8 ( 1 ): 95 . 36872368 10.1038/s41392-022-01302-6 PMC9986243

108 Huang C , Ren S , Chen Y , et al. PD‐L1 methylation restricts PD‐L1/PD‐1 interactions to control cancer immune surveillance . Sci Adv . 2023 ; 9 ( 21 ): eade4186 . 37235656 10.1126/sciadv.ade4186 PMC10219601

109 Hong Y , Kim WJ . DNA methylation markers in lung cancer . Curr Genomics . 2021 ; 22 ( 2 ): 79 ‐ 87 . 34220295 10.2174/1389202921999201013164110 PMC8188581

110 Ptáková N , Martínek P , Holubec L , et al. Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D‐NRG1 gene fusion in prostate cancer by data‐drilling a de‐identified tumor database . Genes Chromosomes Cancer . 2021 ; 60 ( 7 ): 474 ‐ 481 . 33583086 10.1002/gcc.22942

111 Xiao X , He W . Genetic polymorphisms in the TERT‐CLPTM1L region and lung cancer susceptibility in Chinese males . Oncol Lett . 2017 ; 14 ( 2 ): 1588 ‐ 1594 . 28789383 10.3892/ol.2017.6289 PMC5529743

112 Kang JU . Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early‐stage lung adenocarcinoma . Molecular medicine reports . 2013 ; 8 ( 5 ): 1373 ‐ 1378 . 24045431 10.3892/mmr.2013.1686

113 Cheng S , Qian F , Huang Q , Wei L , Fu Y , Du Y . HOXA4, down‐regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells . Cell Death Dis . 2018 ; 9 ( 5 ): 465 . 29700285 10.1038/s41419-018-0497-x PMC5919915

114 Qu H , Xu F , Bai Y , Si X , Yang A . Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer . Indian J Cancer . 2016 ; 53 ( 1 ): 8 ‐ 11 . 27146728 10.4103/0019-509X.180845

115 Wang Y , Huang P , Hu Y , et al. An oncolytic adenovirus delivering TSLC1 inhibits Wnt signaling pathway and tumor growth in SMMC‐7721 xenograft mice model . Acta Biochim Biophy Sin . 2021 ; 53 ( 6 ): 766 ‐ 774 . 10.1093/abbs/gmab048 33928346

116 Sussan TE , Pletcher MT , Murakami Y , Reeves RH . Tumor suppressor in lung cancer 1 (TSLC1) alters tumorigenic growth properties and gene expression . Mol Cancer . 2005 ; 4 : 28 . 16083501 10.1186/1476-4598-4-28 PMC1208945

117 Liu D , Feng X , Wu X , et al. Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, is implicated in the regulation of proliferation, invasion, cell cycle, apoptosis, and tumorigenicity in cutaneous squamous cell carcinoma . Tumour Biol . 2013 ; 34 ( 6 ): 3773 ‐ 3783 . 23812766 10.1007/s13277-013-0961-2

118 Cai Y , Xiong S , Zheng Y , Luo F , Jiang P , Chu Y . Trichosanthin enhances anti‐tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM . Cell Mol Immunol . 2011 ; 8 ( 4 ): 359 ‐ 367 . 21572449 10.1038/cmi.2011.12 PMC4002443

119 Heller G , Fong KM , Girard L , et al. Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas . Oncogene . 2006 ; 25 ( 6 ): 959 ‐ 968 . 16205641 10.1038/sj.onc.1209115

120 Vo TTL , Nguyen TN , Nguyen TT , et al. SHOX2 methylation in Vietnamese patients with lung cancer . Mol Biol Rep . 2022 ; 49 ( 5 ): 3413 ‐ 3421 . 35088378 10.1007/s11033-022-07172-z

121 Li N , Zeng Y , Huang J . Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer . J Cancer Res Clin Oncol . 2020 ; 146 ( 6 ): 1379 ‐ 1393 . 32266538 10.1007/s00432-020-03188-9 PMC11804630

122 Liu J , Bian T , She B , et al. Evaluating the comprehensive diagnosis efficiency of lung cancer, including measurement of SHOX2 and RASSF1A gene methylation . BMC Cancer . 2024 ; 24 ( 1 ): 282 . 38429660 10.1186/s12885-024-12022-1 PMC10908052

123 Xie B , Dong W , He F , Peng F , Zhang H , Wang W . The combination of SHOX2 and RASSF1A DNA methylation had a diagnostic value in pulmonary nodules and early lung cancer . Oncology . 2024 ; 102 ( 9 ): 759 ‐ 774 . 38262380 10.1159/000534275

124 Chen MC , Yang HS , Dong Z , et al. Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer . Cancer Immunol Immunother . 2024 ; 73 ( 11 ): 217 . 39235522 10.1007/s00262-024-03807-1 PMC11377372

125 Su H , Fan G , Huang J , Qiu X . YBX1 regulated by Runx3‐miR‐148a‐3p axis facilitates non‐small‐cell lung cancer progression . Cell Signalling . 2021 ; 85 : 110049 . 34082012 10.1016/j.cellsig.2021.110049

126 Li ZB , Chen X , Yi XJ . Tumor promoting effects of exosomal microRNA‐210 derived from lung cancer cells on lung cancer through the RUNX3/PI3K/AKT signaling pathway axis . J Biol Regul Homeost Agents . 2021 ; 35 ( 2 ): 473 ‐ 484 . 33687910 10.23812/20-570-A

127 Lee JY , Lee JW , Park TG , et al. Runx3 restoration regresses K‐Ras‐activated mouse lung cancers and inhibits recurrence . Cells . 2023 ; 12 ( 20 ): 2438 . 37887282 10.3390/cells12202438 PMC10605764

128 Zhang J , Yang Y , Wei Y , Li L , Wang X , Ye Z . Hsa‐miR‐301a‐3p inhibited the killing effect of natural killer cells on non‐small cell lung cancer cells by regulating RUNX3 . Cancer biomarkers: section A of Disease markers . 2023 ; 37 ( 4 ): 249 ‐ 259 . 10.3233/CBM-220469 PMC12412833 37302028

129 Qin X , Wang XY , Fei JW , Li FH , Han J , Wang HX . MiR‐20a promotes lung tumorigenesis by targeting RUNX3 via TGF‐β signaling pathway . J Biol Regul Homeost Agents . 2020 ; 34 ( 2 ). 10.23812/20-12A 32347076

130 Ono T , Terada F , Okumura M , Chihara T , Hamao K . Impairment of cytokinesis by cancer‐associated DAPK3 mutations . Biochem Biophys Res Commun . 2020 ; 533 ( 4 ): 1095 ‐ 1101 . 33032825 10.1016/j.bbrc.2020.09.078

131 Li Y , Zhu M , Zhang X , Cheng D , Ma X . Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta‐analysis . Drug Des Dev Ther . 2015 ; 9 : 1785 ‐ 1796 . 10.2147/DDDT.S78012 PMC4378294 25848215

132 Zhang Y , Wu J , Huang G , Xu S . Clinicopathological significance of DAPK promoter methylation in non‐small‐cell lung cancer: a systematic review and meta‐analysis . Cancer Manag Res . 2018 ; 10 : 6897 ‐ 6904 . 30588095 10.2147/CMAR.S174815 PMC6296685

133 Yu Q , Guo Q , Chen L , Liu S . Clinicopathological significance and potential drug targeting of CDH1 in lung cancer: a meta‐analysis and literature review . Drug Des Dev Ther . 2015 ; 9 : 2171 ‐ 2178 . 10.2147/DDDT.S78537 PMC4404966 25931811

134 Ye T , Li J , Sun Z , et al. Cdh1 functions as an oncogene by inducing self‐renewal of lung cancer stem‐like cells via oncogenic pathways . Int J Biol Sci . 2020 ; 16 ( 3 ): 447 ‐ 459 . 32015681 10.7150/ijbs.38672 PMC6990901

135 Liu R , Zhang Y , Ding Y , Zhang S , Pan L . Characteristics of TGFBR1‐EGFR‐CTNNB1‐CDH1 signaling axis in wnt‐regulated invasion and migration in lung cancer . Cell Transplant . 2020 ; 29 : 963689720969167 . 33231090 10.1177/0963689720969167 PMC7784602

136 Xu S , Zheng L , Kang L , Xu H , Gao L . microRNA‐let‐7e in serum‐derived exosomes inhibits the metastasis of non‐small‐cell lung cancer in a SUV39H2/LSD1/CDH1‐dependent manner . Cancer Gene Ther . 2021 ; 28 ( 3‐4 ): 250 ‐ 264 . 33299140 10.1038/s41417-020-00216-1

137 Kim JS , Han J , Shim YM , Park J , Kim DH . Aberrant methylation of H‐cadherin (CDH13) promoter is associated with tumor progression in primary nonsmall cell lung carcinoma . Cancer . 2005 ; 104 ( 9 ): 1825 ‐ 1833 . 16177988 10.1002/cncr.21409

138 Feng Q , Hawes SE , Stern JE , et al. DNA methylation in tumor and matched normal tissues from non‐small cell lung cancer patients . Cancer Epidemiol Biomarkers Prev . 2008 ; 17 ( 3 ): 645 ‐ 654 . 18349282 10.1158/1055-9965.EPI-07-2518 PMC2798850

139 Fan X , Tao S , Li Q , Deng B , Tan QY , Jin H . The miR‐23a/27a/24‐2 cluster promotes postoperative progression of early‐stage non‐small cell lung cancer . Molecular therapy oncolytics . 2022 ; 24 : 205 ‐ 217 . 35071744 10.1016/j.omto.2021.12.014 PMC8760463

140 Bradly DP , Gattuso P , Pool M , et al. CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients. Diagnostic molecular pathology : the American journal of surgical pathology , part B . 2012 ; 21 ( 4 ): 207 ‐ 213 . 10.1097/PDM.0b013e31825554b2 23111194

141 Hamad SH , Montgomery SA , Simon JM , et al. TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure‐ and combined‐small cell lung cancer in mice . Oncogene . 2022 ; 41 ( 25 ): 3423 ‐ 3432 . 35577980 10.1038/s41388-022-02348-0 PMC10039451

142 Suzuki T , Sakai S , Ota K , et al. Expression of tumor suppressor FHIT is regulated by the LINC00173‐SNAIL axis in human lung adenocarcinoma . Int J Mol Sci . 2023 ; 24 ( 23 ). 10.3390/ijms242317011 PMC10707390 38069335

143 Jiao Y , Kang G , Pan P , et al. Acetylcholine promotes chronic stress‐induced lung adenocarcinoma progression via α5‐nAChR/FHIT pathway . Cellular and molecular life sciences : CMLS . 2023 ; 80 ( 5 ): 119 . 37029227 10.1007/s00018-023-04742-7 PMC11072774

144 Li R , Todd NW , Qiu Q , et al. Genetic deletions in sputum as diagnostic markers for early detection of stage I non‐small cell lung cancer . Clin Cancer Res . 2007 ; 13 (2 Pt 1): 482 ‐ 487 . 17255269 10.1158/1078-0432.CCR-06-1593

145 Minina VI , Soboleva OA , Glushkov AN , et al. Polymorphisms of GSTM1, GSTT1, GSTP1 genes and chromosomal aberrations in lung cancer patients . J Cancer Res Clin Oncol . 2017 ; 143 ( 11 ): 2235 ‐ 2243 . 28770368 10.1007/s00432-017-2486-3 PMC11819093

146 Haroun RA , Zakhary NI , Mohamed MR , Abdelrahman AM , Kandil EI , Shalaby KA . Assessment of the prognostic value of methylation status and expression levels of FHIT, GSTP1 and p16 in non‐small cell lung cancer in Egyptian patients . Asian Pac J Cancer Prev . 2014 ; 15 ( 10 ): 4281 ‐ 4287 . 24935385 10.7314/apjcp.2014.15.10.4281

147 Xiao J , Wang Y , Wang Z , et al. The relevance analysis of GSTP1 rs1695 and lung cancer in the Chinese Han population . Int J Biol Markers . 2021 ; 36 ( 3 ): 48 ‐ 54 . 34596453 10.1177/17246008211039236

148 Borg M , Wen SWC , Andersen RF , Timm S , Hansen TF , Hilberg O . Methylated circulating tumor DNA in blood as a tool for diagnosing lung cancer: a systematic review and meta‐analysis . Cancers . 2023 ; 15 ( 15 ). 10.3390/cancers15153959 PMC10417522 37568774

149 Gao H , Yang J , He L , et al. The diagnostic potential of SHOX2 and RASSF1A DNA methylation in early lung adenocarcinoma . Front Oncol . 2022 ; 12 : 849024 . 35837113 10.3389/fonc.2022.849024 PMC9273978

150 Du C , Tan L , Xiao X , et al. Detection of the DNA methylation of seven genes contribute to the early diagnosis of lung cancer . J Cancer Res Clin Oncol . 2024 ; 150 ( 2 ): 77 . 38315228 10.1007/s00432-023-05588-z PMC10844440

151 Jin Y , Lu R , Liu F , Jiang G , Wang R , Zheng M . DNA methylation analysis in plasma for early diagnosis in lung adenocarcinoma . Medicine (Baltimore) . 2024 ; 103 ( 28 ): e38867 . 38996143 10.1097/MD.0000000000038867 PMC11245223

152 Ji XY , Li H , Chen HH , Lin J . Diagnostic performance of RASSF1A and SHOX2 methylation combined with EGFR mutations for differentiation between small pulmonary nodules . J Cancer Res Clin Oncol . 2023 ; 149 ( 11 ): 8557 ‐ 8571 . 37097393 10.1007/s00432-023-04745-8 PMC11797607

153 Jiang M , Jia K , Wang L , et al. Alterations of DNA damage response pathway: biomarker and therapeutic strategy for cancer immunotherapy . Acta pharmaceutica Sinica B . 2021 ; 11 ( 10 ): 2983 ‐ 2994 . 34729299 10.1016/j.apsb.2021.01.003 PMC8546664

154 Pongor LS , Tlemsani C , Elloumi F , et al. Integrative epigenomic analyses of small cell lung cancer cells demonstrates the clinical translational relevance of gene body methylation . iScience . 2022 ; 25 ( 11 ): 105338 . 36325065 10.1016/j.isci.2022.105338 PMC9619308

155 Tong L , Sun J , Zhang X , et al. Development of an autoantibody panel for early detection of lung cancer in the Chinese population . Frontiers in medicine . 2023 ; 10 : 1209747 . 38089873 10.3389/fmed.2023.1209747 PMC10711285

156 Chen P , Lu W , Chen T . Seven tumor‐associated autoantibodies as a serum biomarker for primary screening of early‐stage non‐small cell lung cancer . J Clin Lab Anal . 2021 ; 35 ( 11 ): e24020 . 34555232 10.1002/jcla.24020 PMC8605152

157 Luo B , Mao G , Ma H , Chen S . The role of seven autoantibodies in lung cancer diagnosis . J Thorac Dis . 2021 ; 13 ( 6 ): 3660 ‐ 3668 . 34277058 10.21037/jtd-21-835 PMC8264704

158 Wang Z , Xie K , Zhu G , et al. Early detection and stratification of lung cancer aided by a cost‐effective assay targeting circulating tumor DNA (ctDNA) methylation . Respir Res . 2023 ; 24 ( 1 ): 163 . 37330511 10.1186/s12931-023-02449-8 PMC10276518

159 Bajbouj K , Al‐Ali A , Ramakrishnan RK , Saber‐Ayad M , Hamid Q . Histone modification in NSCLC: molecular mechanisms and therapeutic targets . Int J Mol Sci . 2021 ; 22 ( 21 ). 10.3390/ijms222111701 PMC8584007 34769131

160 Chen Y , Liu X , Li Y , Quan C , Zheng L , Huang K . Lung cancer therapy targeting histone methylation: opportunities and challenges . Comput Struct Biotechnol J . 2018 ; 16 : 211 ‐ 223 . 30002791 10.1016/j.csbj.2018.06.001 PMC6039709

161 Chang S , Yim S , Park H . The cancer driver genes IDH1/2, JARID1C/KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism . Exp Mol Med . 2019 ; 51 ( 6 ): 1 ‐ 17 . 10.1038/s12276-019-0230-6 PMC6586683 31221981

162 Guo Y , Wen H , Chen Z , et al. Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation‐driven succinylayion dynamic contibutes to lung cancer . Briefings Bioinf . 2024 ; 25 ( 5 ): bbae415 . 10.1093/bib/bbae415 PMC11343571 39179249

163 Zhou S , Cai Y , Liu X , et al. Role of H2B mono‐ubiquitination in the initiation and progression of cancer . Bull Cancer . 2021 ; 108 ( 4 ): 385 ‐ 398 . 33685627 10.1016/j.bulcan.2020.12.007

164 Khan P , Siddiqui JA , Maurya SK , et al. Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease . Semin Cancer Biol . 2022 ; 83 : 57 ‐ 76 . 33220460 10.1016/j.semcancer.2020.11.006 PMC8218609

165 Martinez‐Useros J , Martin‐Galan M , Florez‐Cespedes M , Garcia‐Foncillas J . Epigenetics of most aggressive solid tumors: pathways, targets and treatments . Cancers . 2021 ; 13 ( 13 ): 3209 . 34198989 10.3390/cancers13133209 PMC8267921

166 Sumimoto H , Takano A , Igarashi T , Hanaoka J , Teramoto K , Daigo Y . Oncogenic epidermal growth factor receptor signal‐induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma . Sci Rep . 2023 ; 13 ( 1 ): 5087 . 36991099 10.1038/s41598-023-32177-4 PMC10060241

167 Yun HS , Lee J , Kim JY , et al. A novel function of HRP‐3 in regulating cell cycle progression via the HDAC‐E2F1‐Cyclin E pathway in lung cancer . Cancer Sci . 2022 ; 113 ( 1 ): 145 ‐ 155 . 34714604 10.1111/cas.15183 PMC8748221

168 Klein BJ , Wang X , Cui G , et al. PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation . Cell Rep . 2016 ; 17 ( 4 ): 1158 ‐ 1170 . 27760318 10.1016/j.celrep.2016.09.056 PMC5125728

169 Ganai SA , Shah BA , Yatoo MA . Histone deacetylase inhibitors as sanguine epitherapeutics against the deadliest lung cancer . Adv Cancer Res . 2023 ; 158 : 163 ‐ 198 . 36990532 10.1016/bs.acr.2022.12.003

170 Mi W , Guan H , Lyu J , et al. YEATS2 links histone acetylation to tumorigenesis of non‐small cell lung cancer . Nat Commun . 2017 ; 8 ( 1 ): 1088 . 29057918 10.1038/s41467-017-01173-4 PMC5651844

171 Sha T , Li J , Sun S , et al. YEATS domain‐containing 2 (YEATS2), targeted by microRNA miR‐378a‐5p, regulates growth and metastasis in head and neck squamous cell carcinoma . Bioengineered . 2021 ; 12 ( 1 ): 7286 ‐ 7296 . 34587874 10.1080/21655979.2021.1977553 PMC8806651

172 Wang H , Lu X , Chen J . Construction and experimental validation of an acetylation‐related gene signature to evaluate the recurrence and immunotherapeutic response in early‐stage lung adenocarcinoma . BMC Med Genet . 2022 ; 15 ( 1 ): 254 . 10.1186/s12920-022-01413-7 PMC9741798 36503492

173 Jeon T , Oh UJ , Min J , Kim C . Gene‐level dissection of chromosome 3q locus amplification in squamous cell carcinoma of the lung using the nCounter assay . Thoracic cancer . 2023 ; 14 ( 26 ): 2635 ‐ 2641 . 37469197 10.1111/1759-7714.15045 PMC10493484

174 Chen F , Qi S , Zhang X , Wu J , Yang X , Wang R . lncRNA PLAC2 activated by H3K27 acetylation promotes cell proliferation and invasion via the activation of Wnt/β‑catenin pathway in oral squamous cell carcinoma . Int J Oncol . 2019 ; 54 ( 4 ): 1183 ‐ 1194 . 30720068 10.3892/ijo.2019.4707 PMC6411352

175 Li YF , Zhang J , Yu L . Circular RNAs regulate cancer onset and progression via Wnt/β‐catenin signaling pathway . Yonsei Med J . 2019 ; 60 ( 12 ): 1117 ‐ 1128 . 31769242 10.3349/ymj.2019.60.12.1117 PMC6881706

176 Lin S , Zhen Y , Guan Y , Yi H . Roles of Wnt/β‐catenin signaling pathway regulatory long non‐coding RNAs in the pathogenesis of non‐small cell lung cancer . Cancer Manag Res . 2020 ; 12 : 4181 ‐ 4191 . 32581590 10.2147/CMAR.S241519 PMC7280066

177 Yang Q , Wang M , Xu J , et al. LINC02159 promotes non‐small cell lung cancer progression via ALYREF/YAP1 signaling . Mol Cancer . 2023 ; 22 ( 1 ): 122 . 37537569 10.1186/s12943-023-01814-x PMC10401734

178 Shang B , Lu F , Jiang S , et al. ALDOC promotes non‐small cell lung cancer through affecting MYC‐mediated UBE2N transcription and regulating Wnt/β‐catenin pathway . Aging . 2023 ; 15 ( 18 ): 9614 ‐ 9632 . 37724906 10.18632/aging.205038 PMC10564444

179 Li J , Xie G , Tian Y , et al. RNA m(6)A methylation regulates dissemination of cancer cells by modulating expression and membrane localization of β‐catenin . Mol Ther . 2022 ; 30 ( 4 ): 1578 ‐ 1596 . 35033632 10.1016/j.ymthe.2022.01.019 PMC9077323

180 Yu W , Hua Y , Qiu H , et al. PD‐L1 promotes tumor growth and progression by activating WIP and β‐catenin signaling pathways and predicts poor prognosis in lung cancer . Cell Death Dis . 2020 ; 11 ( 7 ): 506 . 32632098 10.1038/s41419-020-2701-z PMC7338457

181 Iksen , Pothongsrisit S , Pongrakhananon V . Targeting the PI3K/AKT/mTOR signaling pathway in lung cancer: an update regarding potential drugs and natural products . Molecules . 2021 ; 26 ( 13 ): 4100 . 34279440 10.3390/molecules26134100 PMC8271933

182 Fumarola C , Bonelli MA , Petronini PG , Alfieri RR . Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer . Biochem Pharmacol . 2014 ; 90 ( 3 ): 197 ‐ 207 . 24863259 10.1016/j.bcp.2014.05.011

183 Yu X , Li Y , Jiang G , et al. FGF21 promotes non‐small cell lung cancer progression by SIRT1/PI3K/AKT signaling . Life Sci . 2021 ; 269 : 118875 . 33310036 10.1016/j.lfs.2020.118875

184 Faltus C , Lahnsteiner A , Barrdahl M , et al. Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome‐Wide Association Study (EWAS) . Int J Mol Sci . 2022 ; 23 ( 18 ). 10.3390/ijms231810699 PMC9505874 36142605

185 Larson MH , Pan W , Kim HJ , et al. A comprehensive characterization of the cell‐free transcriptome reveals tissue‐ and subtype‐specific biomarkers for cancer detection . Nat Commun . 2021 ; 12 ( 1 ): 2357 . 33883548 10.1038/s41467-021-22444-1 PMC8060291

186 Zu L , He J , Zhou N , Tang Q , Liang M , Xu S . Identification of multiple organ metastasis‐associated hub mRNA/miRNA signatures in non‐small cell lung cancer . Cell Death Dis . 2023 ; 14 ( 12 ): 798 . 38057344 10.1038/s41419-023-06286-x PMC10700602

187 Alahdal M , Elkord E . Non‐coding RNAs in cancer immunotherapy: Predictive biomarkers and targets . Clin Transl Med . 2023 ; 13 ( 9 ): e1425 . 37735815 10.1002/ctm2.1425 PMC10514379

188 Gilyazova I , Gimalova G , Nizamova A , et al. Non‐coding RNAs as key regulators in lung cancer . Int J Mol Sci . 2023 ; 25 ( 1 ): 560 . 38203731 10.3390/ijms25010560 PMC10778604

189 Kawami M , Takenaka S , Akai M , Yumoto R , Takano M . Characterization of miR‐34a‐induced epithelial‐mesenchymal transition in non‐small lung cancer cells focusing on p53 . Biomolecules . 2021 ; 11 ( 12 ): 1853 . 34944497 10.3390/biom11121853 PMC8699678

190 Hu H , Cheng R , Wang Y , et al. Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47 . J Clin Invest . 2023 ; 133 ( 2 ): e153470 . 36413402 10.1172/JCI153470 PMC9843062

191 Gardner EE , Lok BH , Schneeberger VE , et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2‐SLFN11 axis . Cancer Cell . 2017 ; 31 ( 2 ): 286 ‐ 299 . 28196596 10.1016/j.ccell.2017.01.006 PMC5313262

192 Li C , Lv Y , Shao C , et al. Tumor‐derived exosomal lncRNA GAS5 as a biomarker for early‐stage non‐small‐cell lung cancer diagnosis . J Cell Physiol . 2019 ; 234 ( 11 ): 20721 ‐ 20727 . 31032916 10.1002/jcp.28678

193 Tan Q , Zuo J , Qiu S , et al. Identification of circulating long non‐coding RNA GAS5 as a potential biomarker for non‐small cell lung cancer diagnosisnon‐small cell lung cancer, long non‐coding RNA, plasma, GAS5, biomarker . Int J Oncol . 2017 ; 50 ( 5 ): 1729 ‐ 1738 . 28339045 10.3892/ijo.2017.3925

194 Chen Y , Li Z , Chen X , Zhang S . Long non‐coding RNAs: from disease code to drug role . Acta pharmaceutica Sinica B . 2021 ; 11 ( 2 ): 340 ‐ 354 . 33643816 10.1016/j.apsb.2020.10.001 PMC7893121

195 Liu T , Han C , Fang P , et al. Long non‐coding RNAs in lung cancer: implications for lineage plasticity‐mediated TKI resistance . Cell Mol Life Sci . 2021 ; 78 ( 5 ): 1983 ‐ 2000 . 33170304 10.1007/s00018-020-03691-9 PMC7965852

196 Wang Q , Wu J , Huang H , et al. lncRNA LIFR‐AS1 suppresses invasion and metastasis of non‐small cell lung cancer via the miR‐942‐5p/ZNF471 axis . Cancer Cell Int . 2020 ; 20 : 180 . 32489316 10.1186/s12935-020-01228-5 PMC7245777

197 Wei K , Ma Z , Yang F , et al. M2 macrophage‐derived exosomes promote lung adenocarcinoma progression by delivering miR‐942 . Cancer Lett . 2022 ; 526 : 205 ‐ 216 . 34838826 10.1016/j.canlet.2021.10.045

198 El‐Aal AEA , Elshafei A , Ismail MY , El‐Shafey MM . Identification of miR‐106b‐5p, miR‐601, and miR‐760 expression and their clinical values in non‐small cell lung cancer (NSCLC) patients' serum . Pathol Res Pract . 2023 ; 248 : 154663 . 37429174 10.1016/j.prp.2023.154663

199 Davenport ML , Echols JB , Silva AD , et al. miR‐31 displays subtype specificity in lung cancer . Cancer Res . 2021 ; 81 ( 8 ): 1942 ‐ 1953 . 33558335 10.1158/0008-5472.CAN-20-2769 PMC8137562

200 Edmonds MD , Boyd KL , Moyo T , et al. MicroRNA‐31 initiates lung tumorigenesis and promotes mutant KRAS‐driven lung cancer . J Clin Invest . 2016 ; 126 ( 1 ): 349 ‐ 364 . 26657862 10.1172/JCI82720 PMC4701567

201 Simiene J , Dabkeviciene D , Stanciute D , et al. Potential of miR‐181a‐5p and miR‐630 as clinical biomarkers in NSCLC . BMC Cancer . 2023 ; 23 ( 1 ): 857 . 37697308 10.1186/s12885-023-11365-5 PMC10496384

202 Chen Y , Zhang Y . CircDLG1 promotes malignant development of non‐small cell lung cancer through regulation of the miR‐630/CENPF axis . Strahlenther Onkol . 2023 ; 199 ( 2 ): 169 ‐ 181 . 35748916 10.1007/s00066-022-01965-8

203 Lv H , Yu J , Zhang H , et al. MicroRNA‐631 deriving from bone marrow mesenchymal stem cell exosomes facilitates the malignant behavior of non‐small cell lung cancer via modulating the E2F family of transcription factor 2/phosphatidylinositol 3‐kinase/Akt signaling pathway . Bioengineered . 2022 ; 13 ( 4 ): 8382 ‐ 8395 . 35353027 10.1080/21655979.2022.2036891 PMC9161988

204 Zhang ZW , An Y , Teng CB . [The roles of miR‐17‐92 cluster in mammal development and tumorigenesis] . Yi chuan = Hereditas . 2009 ; 31 ( 11 ): 1094 ‐ 1100 . 19933089 10.3724/sp.j.1005.2009.01094

205 Zhu L , Sun L , Xu G , et al. The diagnostic value of has_circ_0006423 in non‐small cell lung cancer and its role as a tumor suppressor gene that sponges miR‐492 . Sci Rep . 2022 ; 12 ( 1 ): 13722 . 35962012 10.1038/s41598-022-17816-6 PMC9374755

206 Zhu SY , Zhang ZX , Gu L , et al. CircFBXW7 inhibits proliferation, migration, and invasion of nonsmall cell lung cancer cells by regulating miR‐492 . J Oncol . 2022 ; 2022 : 8699359 . 36117850 10.1155/2022/8699359 PMC9477579

207 Duan X , Qiao S , Li D , et al. Circulating miRNAs in serum as biomarkers for early diagnosis of non‐small cell lung cancer . Front Genet . 2021 ; 12 : 673926 . 34306018 10.3389/fgene.2021.673926 PMC8299278

208 Lai XN , Li J , Tang LB , Chen WT , Zhang L , Xiong LX . MiRNAs and LncRNAs: dual roles in TGF‐β signaling‐regulated metastasis in lung cancer . Int J Mol Sci . 2020 ; 21 ( 4 ): 1193 . 32054031 10.3390/ijms21041193 PMC7072809

209 Goyal B , Yadav SRM , Awasthee N , Gupta S , Kunnumakkara AB , Gupta SC . Diagnostic, prognostic, and therapeutic significance of long non‐coding RNA MALAT1 in cancer . Biochimica et biophysica acta Reviews on cancer . 2021 ; 1875 ( 2 ): 188502 . 33428963 10.1016/j.bbcan.2021.188502

210 Esfandi F , Taheri M , Omrani MD , et al. Expression of long non‐coding RNAs (lncRNAs) has been dysregulated in non‐small cell lung cancer tissues . BMC Cancer . 2019 ; 19 ( 1 ): 222 . 30866866 10.1186/s12885-019-5435-5 PMC6417110

211 Wang C , Tan S , Li J , Liu WR , Peng Y , Li W . CircRNAs in lung cancer ‐ biogenesis, function and clinical implication . Cancer Lett . 2020 ; 492 : 106 ‐ 115 . 32860847 10.1016/j.canlet.2020.08.013

212 Su C , Han Y , Zhang H , et al. CiRS‐7 targeting miR‐7 modulates the progression of non‐small cell lung cancer in a manner dependent on NF‐κB signalling . J Cell Mol Med . 2018 ; 22 ( 6 ): 3097 ‐ 3107 . 29532994 10.1111/jcmm.13587 PMC5980210

213 Li J , Zhang Q , Jiang D , Shao J , Li W , Wang C . CircRNAs in lung cancer‐ role and clinical application . Cancer Lett . 2022 ; 544 : 215810 . 35780929 10.1016/j.canlet.2022.215810

214 Saliminejad K , Khorram Khorshid HR , Soleymani Fard S , Ghaffari SH . An overview of microRNAs: Biology, functions, therapeutics, and analysis methods . J Cell Physiol . 2019 ; 234 ( 5 ): 5451 ‐ 5465 . 30471116 10.1002/jcp.27486

215 Li B , Cao Y , Sun M , Feng H . Expression, regulation, and function of exosome‐derived miRNAs in cancer progression and therapy . FASEB J . 2021 ; 35 ( 10 ): e21916 . 34510546 10.1096/fj.202100294RR

216 Kim JS , Kim EJ , Lee S , et al. MiR‐34a and miR‐34b/c have distinct effects on the suppression of lung adenocarcinomas . Exp Mol Med . 2019 ; 51 ( 1 ): 1 ‐ 10 . 10.1038/s12276-018-0203-1 PMC6353903 30700696

217 Dezfuli NK , Alipoor SD , Dalil Roofchayee N , et al. Evaluation expression of miR‐146a and miR‐155 in Non‐Small‐Cell Lung Cancer Patients . Front Oncol . 2021 ; 11 : 715677 . 34790566 10.3389/fonc.2021.715677 PMC8591170

218 Wu J , Shen Z . Exosomal miRNAs as biomarkers for diagnostic and prognostic in lung cancer . Cancer Med . 2020 ; 9 ( 19 ): 6909 ‐ 6922 . 32779402 10.1002/cam4.3379 PMC7541138

219 Ulivi P , Zoli W . miRNAs as non‐invasive biomarkers for lung cancer diagnosis . Molecules . 2014 ; 19 ( 6 ): 8220 ‐ 8237 . 24941344 10.3390/molecules19068220 PMC6271142

220 O'Farrell HE , Bowman RV , Fong KM , Yang IA . Plasma extracellular vesicle miRNAs can identify lung cancer, current smoking status, and stable COPD . Int J Mol Sci . 2021 ; 22 ( 11 ): 5803 . 34071592 10.3390/ijms22115803 PMC8198071

221 Zhou C , Chen Z , Zhao L , et al. A novel circulating miRNA‐based signature for the early diagnosis and prognosis prediction of non‐small‐cell lung cancer . J Clin Lab Anal . 2020 ; 34 ( 11 ): e23505 . 33463758 10.1002/jcla.23505 PMC7676218

222 Li K , Gong Q , Xiang XD , et al. HNRNPA2B1‐mediated m(6)A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non‐small cell lung cancer by regulating miR‐21‐5p/PTEN axis . J Transl Med . 2023 ; 21 ( 1 ): 382 . 37308993 10.1186/s12967-023-04190-8 PMC10258935

223 Qian S , Liu J , Liao W , Wang F . METTL3 promotes non‐small‐cell lung cancer growth and metastasis by inhibiting FDX1 through copper death‐associated pri‐miR‐21‐5p maturation . Epigenomics . 2023 ; 15 ( 23 ): 1237 ‐ 1255 . 38126112 10.2217/epi-2023-0230

224 Sultana A , Alam MS , Liu X , et al. Single‐cell RNA‐seq analysis to identify potential biomarkers for diagnosis, and prognosis of non‐small cell lung cancer by using comprehensive bioinformatics approaches . Transl Oncol . 2023 ; 27 : 101571 . 36401966 10.1016/j.tranon.2022.101571 PMC9676382

225 Li J , Zhong X , Zhao Y , Shen J , Xiao Z , Pilapong C . Acacetin inhibited non‐small‐cell lung cancer (NSCLC) cell growth via upregulating miR‐34a in vitro and in vivo . Sci Rep . 2024 ; 14 ( 1 ): 2348 . 38287075 10.1038/s41598-024-52896-6 PMC10824707

226 Yang J , Xu J , Wang W , Zhang B , Yu X , Shi S . Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets . Signal transduction and targeted therapy . 2023 ; 8 ( 1 ): 210 . 37217462 10.1038/s41392-023-01480-x PMC10203321

227 Dai E , Zhu Z , Wahed S , Qu Z , Storkus WJ , Guo ZS . Epigenetic modulation of antitumor immunity for improved cancer immunotherapy . Mol Cancer . 2021 ; 20 ( 1 ): 171 . 34930302 10.1186/s12943-021-01464-x PMC8691037

228 Chen H , Yao J , Bao R , et al. Cross‐talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer . Mol Cancer . 2021 ; 20 ( 1 ): 29 . 33557837 10.1186/s12943-021-01322-w PMC7869236

229 Zhang J , Gao J , Hu M , et al. Integrated investigation of the clinical implications and targeted landscape for RNA methylation modifications in hepatocellular carcinoma . Eur J Med Res . 2023 ; 28 ( 1 ): 46 . 36707911 10.1186/s40001-023-01016-7 PMC9881284

230 Fernández‐Barrena MG , Arechederra M , Colyn L , Berasain C , Avila MA . Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg . JHEP reports : innovation in hepatology . 2020 ; 2 ( 6 ): 100167 . 33134907 10.1016/j.jhepr.2020.100167 PMC7585149

231 Li X , Peng X , Zhang C , et al. Bladder cancer‐derived small extracellular vesicles promote tumor angiogenesis by inducing hbp‐related metabolic reprogramming and SerRS O‐GlcNAcylation in endothelial cells . Advanced science (Weinheim, Baden‐Wurttemberg, Germany) . 2022 ; 9 ( 30 ): e2202993 . 36045101 10.1002/advs.202202993 PMC9596856

232 Park M , Kim D , Ko S , Kim A , Mo K , Yoon H . Breast cancer metastasis: mechanisms and therapeutic implications . Int J Mol Sci . 2022 ; 23 ( 12 ): 6806 . 35743249 10.3390/ijms23126806 PMC9224686

233 Qian Y , Gong Y , Fan Z , et al. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma . J Hematol Oncol . 2020 ; 13 ( 1 ): 130 . 33008426 10.1186/s13045-020-00958-3 PMC7532113

234 Kochumon S , Al‐Sayyar A , Jacob T , et al. TGF‐β and TNF‐α interaction promotes the expression of MMP‐9 through H3K36 dimethylation: implications in breast cancer metastasis . Front Immunol . 2024 ; 15 : 1430187 . 39351229 10.3389/fimmu.2024.1430187 PMC11439675

235 Chatterjee B , Saha P , Bose S , et al. MicroRNAs: as critical regulators of tumor‐ associated macrophages . Int J Mol Sci . 2020 ; 21 ( 19 ): 7117 . 32992449 10.3390/ijms21197117 PMC7582892

236 Najem A , Soumoy L , Sabbah M , et al. Understanding molecular mechanisms of phenotype switching and crosstalk with TME to reveal new vulnerabilities of melanoma . Cells . 2022 ; 11 ( 7 ): 1157 . 35406721 10.3390/cells11071157 PMC8997563

237 Alipoor SD , Chang H . Exosomal miRNAs in the tumor microenvironment of multiple myeloma . Cells . 2023 ; 12 ( 7 ): 1030 . 37048103 10.3390/cells12071030 PMC10092980

238 Lambrechts D , Wauters E , Boeckx B , et al. Phenotype molding of stromal cells in the lung tumor microenvironment . Nat Med . 2018 ; 24 ( 8 ): 1277 ‐ 1289 . 29988129 10.1038/s41591-018-0096-5

239 Schamschula E , Lahnsteiner A , Assenov Y , et al. Disease‐related blood‐based differential methylation in cystic fibrosis and its representation in lung cancer revealed a regulatory locus in PKP3 in lung epithelial cells . Epigenetics . 2022 ; 17 ( 8 ): 837 ‐ 860 . 34415821 10.1080/15592294.2021.1959976 PMC9423854

240 O'Leary K , Shia A , Schmid P . Epigenetic regulation of EMT in non‐small cell lung cancer . Curr Cancer Drug Targets . 2018 ; 18 ( 1 ): 89 ‐ 96 . 28176646 10.2174/1568009617666170203162556

241 Nicorescu I , Dallinga GM , de Winther MPJ , Stroes ESG , Bahjat M . Potential epigenetic therapeutics for atherosclerosis treatment . Atherosclerosis . 2019 ; 281 : 189 ‐ 197 . 30340764 10.1016/j.atherosclerosis.2018.10.006

242 Franco F , Jaccard A , Romero P , Yu YR , Ho PC . Metabolic and epigenetic regulation of T‐cell exhaustion . Nature metabolism . 2020 ; 2 ( 10 ): 1001 ‐ 1012 . 10.1038/s42255-020-00280-9 32958939

243 Su S , Chen J , Yao H , et al. CD10(+)GPR77(+) cancer‐associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness . Cell . 2018 ; 172 ( 4 ): 841 ‐ 856.e816 . 29395328 10.1016/j.cell.2018.01.009

244 Chen Y , Zhu WG . Biological function and regulation of histone and non‐histone lysine methylation in response to DNA damage . Acta Biochim Biophy Sin . 2016 ; 48 ( 7 ): 603 ‐ 616 . 10.1093/abbs/gmw050 27217472

245 Xia M , Wang B , Wang Z , Zhang X , Wang X . Epigenetic regulation of NK cell‐mediated antitumor immunity . Front Immunol . 2021 ; 12 : 672328 . 34017344 10.3389/fimmu.2021.672328 PMC8129532

246 Zhang Y , Good‐Jacobson KL . Epigenetic regulation of B cell fate and function during an immune response . Immunol Rev . 2019 ; 288 ( 1 ): 75 ‐ 84 . 30874352 10.1111/imr.12733

247 Weber R , Fleming V , Hu X , et al. Myeloid‐derived suppressor cells hinder the anti‐cancer activity of immune checkpoint inhibitors . Front Immunol . 2018 ; 9 : 1310 . 29942309 10.3389/fimmu.2018.01310 PMC6004385

248 Lo YMD , Han DSC , Jiang P , Chiu RWK . Epigenetics, fragmentomics, and topology of cell‐free DNA in liquid biopsies . Science . 2021 ; 372 ( 6538 ): eaaw3616 . 33833097 10.1126/science.aaw3616

249 Jin S , Zhu D , Shao F , et al. Efficient detection and post‐surgical monitoring of colon cancer with a multi‐marker DNA methylation liquid biopsy . Proc Nat Acad Sci USA . 2021 ; 118 ( 5 ): e2017421118 . 33495330 10.1073/pnas.2017421118 PMC7865146

250 Li Y , Seto E . HDACs and HDAC inhibitors in cancer development and therapy . Cold Spring Harb Perspect Med . 2016 ; 6 ( 10 ): a026831 . 27599530 10.1101/cshperspect.a026831 PMC5046688

251 Casagrande GMS , Silva MO , Reis RM , Leal LF . Liquid biopsy for lung cancer: up‐to‐date and perspectives for screening programs . Int J Mol Sci . 2023 ; 24 ( 3 ): 2505 . 36768828 10.3390/ijms24032505 PMC9917347

252 Xu RH , Wei W , Krawczyk M , et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma . Nat Mater . 2017 ; 16 ( 11 ): 1155 ‐ 1161 . 29035356 10.1038/nmat4997

253 Dietrich D , Weider S , de Vos L , et al. Circulating cell‐free SEPT9 DNA methylation in blood is a biomarker for minimal residual disease detection in head and neck squamous cell carcinoma patients . Clin Chem . 2023 ; 69 ( 9 ): 1050 ‐ 1061 . 37477541 10.1093/clinchem/hvad084

254 Moqri M , Herzog C , Poganik JR , et al. Biomarkers of aging for the identification and evaluation of longevity interventions . Cell . 2023 ; 186 ( 18 ): 3758 ‐ 3775 . 37657418 10.1016/j.cell.2023.08.003 PMC11088934

255 García‐Giménez JL , Mena‐Mollá S , Beltrán‐García J , Sanchis‐Gomar F . Challenges in the analysis of epigenetic biomarkers in clinical samples . Clin Chem Lab Med . 2017 ; 55 ( 10 ): 1474 ‐ 1477 . 28301317 10.1515/cclm-2016-1162

256 Giri AK , Aittokallio T . DNMT inhibitors increase methylation in the cancer genome . Front Pharmacol . 2019 ; 10 : 385 . 31068808 10.3389/fphar.2019.00385 PMC6491738

257 Tellez CS , Picchi MA , Juri D , et al. Chromatin remodeling by the histone methyltransferase EZH2 drives lung pre‐malignancy and is a target for cancer prevention . Clinical epigenetics . 2021 ; 13 ( 1 ): 44 . 33632299 10.1186/s13148-021-01034-4 PMC7908796

258 Reggiani F , Talarico G , Gobbi G , et al. BET inhibitors drive Natural Killer activation in non‐small cell lung cancer via BRD4 and SMAD3 . Nat Commun . 2024 ; 15 ( 1 ): 2567 . 38519469 10.1038/s41467-024-46778-8 PMC10960013

259 Duan L , Tadi MJ , Maki CG . CSE1L is a negative regulator of the RB‐DREAM pathway in p53 wild‐type NSCLC and can be targeted using an HDAC1/2 inhibitor . Sci Rep . 2023 ; 13 ( 1 ): 16271 . 37759078 10.1038/s41598-023-43218-3 PMC10533896

260 Gaździcka J , Świętek A , Hudy D , et al. Concentration of secreted frizzled‐related proteins (SFRPs) in non‐small cell lung carcinoma subtypes—a preliminary study . Current oncology (Toronto, Ont) . 2023 ; 30 ( 11 ): 9968 ‐ 9980 . 37999144 10.3390/curroncol30110724 PMC10670352

261 Pawlak A , Chybicka K , Zioło E , Strządała L , Kałas W . The contrasting delayed effects of transient exposure of colorectal cancer cells to decitabine or azacitidine . Cancers . 2022 ; 14 ( 6 ): 1530 . 35326680 10.3390/cancers14061530 PMC8945888

262 Sunaga N , Kaira K , Shimizu K , et al. The oncogenic role of LGR6 overexpression induced by aberrant Wnt/β‐catenin signaling in lung cancer . Thoracic cancer . 2024 ; 15 ( 2 ): 131 ‐ 141 . 38014454 10.1111/1759-7714.15169 PMC10788478

263 He T , Gao Y , Fang Y , et al. The HDAC inhibitor GCJ‐490A suppresses c‐Met expression through IKKα and overcomes gefitinib resistance in non‐small cell lung cancer . Cancer Biol Med . 2022 ; 19 ( 8 ): 1172 ‐ 1192 . 35188360 10.20892/j.issn.2095-3941.2021.0130 PMC9425179

264 Yang L , Jin M , Jeong KW . Histone H3K4 methyltransferases as targets for drug‐resistant cancers . Biology . 2021 ; 10 ( 7 ): 581 . 34201935 10.3390/biology10070581 PMC8301125

265 Li Y , Li M , Jin F , Liu J , Chen M , Yin J . DNAJC12 promotes lung cancer growth by regulating the activation of β‑catenin . Int J Mol Med . 2021 ; 47 ( 6 ): 105 . 33907820 10.3892/ijmm.2021.4938 PMC8057298

266 Hao A , Wang Y , Stovall DB , Wang Y , Sui G . Emerging roles of LncRNAs in the EZH2‐regulated oncogenic network . Int J Biol Sci . 2021 ; 17 ( 13 ): 3268 ‐ 3280 . 34512145 10.7150/ijbs.63488 PMC8416728

267 Zhang J , Liu L , Wei X , et al. Pan‐cancer characterization of ncRNA synergistic competition uncovers potential carcinogenic biomarkers . PLoS Comput Biol . 2023 ; 19 ( 10 ): e1011308 . 37812646 10.1371/journal.pcbi.1011308 PMC10586676

268 Khan FB , Uddin S , Elderdery AY , et al. Illuminating the molecular intricacies of exosomes and ncRNAs in cardiovascular diseases: prospective therapeutic and biomarker potential . Cells . 2022 ; 11 ( 22 ): 3664 . 36429092 10.3390/cells11223664 PMC9688392