Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies.

INTRODUCTION

The tumor‐suppressor protein p53 is known as the guardian of the genome. p53 is involved in the activation of various biological responses, mainly including cell cycle arrest, DNA repair, and apoptosis. 1 , 2 , 3 , 4 Activation of p53 is mediated by multiple stress signals, including hypoxia, DNA damage, and strong proliferative signals. 5 , 6 , 7 , 8 Inhibition of MDM2 and its cognate complex protein MDMX is the most important regulatory pathway for p53 activation. 9 Stress signals can upregulate the expression of ATM, ATR, and other proteins through sensory proteins, and reduce the expression of MDM2. 10 , 11 When the proto‐oncogene is activated, ARF is activated and the inhibition of MDM2 expression is enhanced. 12 , 13 Second, some upstream factors can also directly activate p53, for example, ATM and ATR proteins can promote the phosphorylation of p53 through CHK1/CHK2 or directly and increase the expression level of p53. 14 , 15 Dysregulation of p53 function can be detected in approximately 90% of cancers, including TP53 mutations or abnormal activation of other upstream factors. 16 , 17 Stress signals such as DNA damage, cellular hypoxia, reactive oxygen species (ROS) damage, and activation of proto‐oncogenes increase the amount and activity of p53 after transcription by promoting p53 phosphorylation and inhibiting p53 ubiquitination. 18 , 19 , 20 , 21 , 22 Activated p53 forms a tetramer and binds to a variety of target genes and promotes their transcription, thereby inhibiting cell carcinogenesis. 7 , 23 , 24

Abnormalities in the p53 pathway interfere with the normal cell cycle, programmed cell death, DNA repair, senescence, and angiogenesis, ultimately leading to cancer progression. 25 , 26 , 27 , 28 , 29 , 30 Restoring normal expression and activity of p53 is a potential strategy for the treatment of various cancers. 31 Currently, many compounds that can reactivate p53 or destabilize mutant p53, such as APR‐246 and COTI‐2, have been approved for clinical trials. 32 At the same time, MDM2 inhibitors have also been related to research, and inhibition of MDM2–p53 interaction has become a possible therapy. 33 , 34 , 35 , 36 , 37 However, the corresponding research has mainly focused on the mutation site of TP53 or p53, and the relevant clinical transformation is still in its infancy. 38 Although different mutant p53 (mut‐p53)‐targeted therapeutic strategies have been developed, there are still no approved drugs for the clinical treatment of mut‐p53‐expressing cancers. 39 At the same time, as a nuclear transcription factor, p53 does not have typical drug target characteristics, so it has long been considered untreatable. Although many p53‐based therapies have been explored and studied in the past three decades, few p53 drug development programs have reached the advanced clinical trial stage, and none of them have been approved by the United States Food and Drug Administration until now. 40

TP53‐regulated inhibitor of apoptosis 1 (TRIAP1) is a novel p53 downstream gene that mediates the antiapoptotic activity of p53. TRIAP1 expression is tightly regulated by p53, and phosphorylation at different sites on p53 can significantly affect TRIAP1 expression. 41 The translation process of TRIAP1 is regulated by various noncoding RNAs (ncRNAs). 42 Numerous studies have shown that TRIAP1 is a novel tumor diagnostic and prognostic marker. TRIAP1 is abnormally highly expressed in a variety of tumors and has a cancer‐promoting effect. 43 TRIAP1 expression was significantly higher in multiple drug‐resistant cancer cell lines (doxorubicin (DOX), cisplatin (DDP), tamoxifen (TAM), and etoposide (VP‐16)) than in corresponding drug‐sensitive cell lines. 44 In addition, as an independent prognostic factor, TRIAP1 overexpression often predicts poorer overall survival (OS) and disease‐free survival (DFS) in patients, and more advanced histological grade. 45

Despite the difficulties, targeting the p53 pathway remains a top priority in cancer research. Therefore, we systematically classified the important or new gene targets in the p53 pathway in recent years and reviewed their molecular mechanisms in the p53 pathway. At the same time, our work also sorts out the clinical value of these gene targets and the corresponding targeted therapy research. Finally, this study outlines the shortcomings of current related research, aiming to provide direction and a basis for further in‐depth research.

THE STRUCTURE, MUTATION, AND MODIFICATION OF p53

p53 is a specific transcription factor consisting of 393 amino acids with 7 functional domains. 46 , 47 p53 is encoded by the TP53 gene, which includes 11 exons and 10 introns. As shown in Figure 1 , p53 is divided into 7 functional domains from N‐terminal to C‐terminal, transactivation domain (TAD) ‐1, TAD‐2, proline‐rich domain (PRD), DNA‐binding domain (DBD), hinge domain (HD), oligomerization domain (OD), and C‐terminal regulatory domain (CTR). 47 , 48

For a long time, p53 was considered to be the only expression product of the TP53 gene. However, under physiological conditions, 12 p53 subtypes have been discovered so far, and each subtype uses different promoters, splicing events, and alternative translation initiation sites to distinguish each other. 49 , 50 The p53 isoforms are divided into α, β, and γ according to the difference of the C‐terminus. Among them, the α class is the longest, and it contains all the domains of the C‐terminus of p53. 51 The β class retains the α nuclear localization sequence, and at the same time adds a unique sequence of 10 amino acids derived from exon 9b, but deletes most of the OD domain after amino acid 331 and the entire CTR domain. 52 The γ class also lacks the sequence after amino acid 331 and correspondingly increases the unique sequence of 15 amino acids derived from exon 9b. 53

According to the amino acid sequence of the N‐terminal deletion, the p53 subtypes are divided into four types: TAp53, Δ40p53, Δ133p53, and Δ160p53. TAp53 is the complete p53, while Δ40p53 is the result of alternative splicing of the original p53, which lacks the first 39 amino acids and therefore lacks the TAD‐1 domain, but still retains all the TAD‐2 and DBD domains. 54 The Δ133p53 isoform lacks the first 132 amino acids and thus lacks TAD‐1, TAD‐2, PRD, and part of the DBD. 55 The Δ160p53 isoform lacks the first 159 amino acids and thus lacks TAD‐1, TAD‐2, PRD, and more DBD regions. 56 Deletions and changes between subtypes will affect the function of the p53 protein, for example, the subtypes missing the C‐terminus will affect the orientation of p53 to target genes. p53β enhances the transactivation of p21 and Bax promoters in breast cancer (BrC). In contrast, p53γ can only stimulate the transactivation activity of the Bax promoter. 57 Isoforms lacking the N‐terminus tend to have a reduced ability to activate transcription of p53 target genes due to loss of TAD. However, Δ133p53 and Δ160p53 further delete the ubiquitination site at the N‐terminus, which reduces the proteasome degradation rate and improves stability. 49 , 58 At the same time, complexes can also be formed between different p53 subtypes to positively or negatively regulate p53‐dependent gene expression. 1

Functional changes and prognostic value of mutant p53

About 50% of cancers with confirmed p53 inactivation are caused by point mutations in the TP53 gene. 16 , 39 Most of them are missense mutations in DBD, which make p53 lose its DNA binding activity, thereby promoting tumor development. 59 For example, in diffuse large B‐cell lymphoma (DLBCL), p53 mutations are associated with poorer OS and PFS. 60 Similarly, missense mutations in TAD often lead to poor prognosis in cancer patients. For example, in H1299 cells, mut‐TAD (L22Q and W23S) can inhibit the phosphorylation of p53 Ser20, weaken the activation of p53 by PLK3, and make p53 occur Dominant oncogenic alteration. 61 There are also some mutations and some mutations only make p53 easy to aggregate, eventually forming inactive amyloid aggregates. At this time, if the aggregation of p53 proteins can be prevented, part of the function of p53 can be preserved. 62

Missense mutations in the p53 DBD also affect the interaction of p53 with other proteins. For example, mut‐DBD (R248Q and R249S) can lead to an enhanced antifolding effect of Hsp70/Hdj1 on mut‐p53, making p53 more susceptible to breakdown by Hsp70/Hdj1. The DNA‐binding loop dissociates, leaving p53 in a hypoactive, deprotected state. However, mut‐DBD‐R175H attenuates Hsp70/Hdj1 antifolding and stabilizes p53 from degradation. 63

But now more and more studies have found that some nondestructive mutations in p53 DBD can be used as favorable factors for cancer prognosis. For example, partial missense mutations in the p53 DBD have been associated with prolonged PFS in metastatic colorectal cancer (mCRC) patients with bevacizumab‐based therapy. 64 Missense mutations in DBD (including R273X, Y220X, H193, H179X, and R175H) are associated with prolonged OS and PFS in resectable esophageal squamous cell carcinoma (ESCC). 65 Other mutations in the DBD have vastly different effects on p53 function. It is speculated that this may be due to nondestructive mutations that lead to structural changes in DBD and enhanced transcriptional activity of some tumor suppressor genes, leading to enhanced sensitivity of cancer cells to treatment. 64 However, the mechanism still needs more prospective research to discover and confirm.

Posttranslational modifications of p53

An additional ∼40% of cancers with confirmed p53 inactivation were due to alterations in p53 regulators. 66 This process involves a variety of posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, and other modifications, to jointly regulate the activity and stability of p53. 67 , 68 , 69

Phosphorylation modifications of p53

Phosphorylation mostly occurs at Ser6, Ser9, Ser15, Thr18, Ser20, Ser33, Ser37, Ser46, Thr55, and Thr81 on the p53 N‐terminal domain TAD‐1 and TAD‐2. 70 , 71 Other sites on p53 can also be phosphorylated, such as Ser313, Ser314, Ser315, Ser366, Ser376, Thr377, Ser378, Thr387, and Ser392. 72 , 73 The phosphorylation of p53 can be mediated by various protein kinases, including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3‐related protein (ATR), DNA‐dependent protein kinase (DNA‐PK), checkpoint kinase‐1 (Chk1), checkpoint kinase‐2 (Chk2), and c‐Jun N‐terminal kinase. 13 , 74 , 75 , 76 , 77 The protein phosphatase magnesium‐dependent 1 delta mediates the dephosphorylation process of p53. 78

Phosphorylation increases the stability of p53 through multiple mechanisms. For example, phosphorylation on Thr81 changes the conformation of p53 and inhibits the binding of p53 to the ubiquitinase MDM2. 79 Phosphorylation can also improve the affinity of p53 to the acetylase p300/CRB and compete for the lysine site on p53 through acetylation and ubiquitination, thereby improving the stability of p53 and facilitating the biological function of p53. 18 , 80 At the same time, depending on the position of the phosphorylated residue, the orientation of p53 binding to target genes will be changed. For example, the phosphorylation of p53 Ser46 is closely related to the induction of apoptosis. 81 Phosphorylation of p53 Ser42 plays an important role in cell survival after DNA damage. 82

Many studies have confirmed that the phosphorylation site of p53 can affect the prognosis and pathological conditions of cancer patients. In general, patients with high levels of p53 phosphorylation have a better prognosis. Hepatocellular carcinoma (HCC) patients with high levels of p53 Ser46 phosphorylation have relatively longer OS. 83 BCa patients with high p53 Thr81 phosphorylation have relatively longer OS with lower grade and lower tumor size. 84 BrC, CRC, and glioma patients with high levels of p53 Ser366 phosphorylation have relatively longer OS. 72 HCC patients with high levels of p53 Ser392 phosphorylation have relatively longer OS and recurrence‐free survival (RFS). 85 In contrast, BCa and non‐small‐cell lung cancer (NSCLC) patients with high levels of p53 Ser315 phosphorylation have relatively shorter OS and later TNM stage and histological grade. 86 , 87

Acetylation modifications of p53

Acetylation of p53 occurs on the lysine residues in the p53 CTR domain, including Lys101, Lys120, Lys139, Lys164, Lys305, Lys319, Lys320, Lys370, Lys372, Lys373, Lys381, Lys382, Lys386, and so on. This is followed by lysine residues in the OD and DBD domains. 88 , 89 p53 acetylation can be promoted by acetyltransferases such as p300/CREB‐binding protein (CBP), p300/CBP‐associated factor (PCAF), and 60 kDa taf interactive protein (TIP60), 18 , 90 , 91 but can also be blocked by deacetylases such as histone deacetylase (HDAC) and Sirtuin (SIRT). 92 , 93

The acetylation of p53 can be activated by factors such as DNA damage and genotoxic stress, which is similar to phosphorylation. Phosphorylation of p53 can increase the affinity of p53 to the acetylase p300 and then significantly promote acetylation. 94 The acetylation of p53 can compete with ubiquitination, and the acetyl group competes with ubiquitin for lysine residues on the CTR, which can improve the stability of p53 and greatly activate the activity of the DBD domain. 88 , 95 The site and degree of p53 acetylation will affect the function of p53. For example, acetylation of both Lys120 and Lys164 on the DBD domain of p53 helps induce cell cycle arrest, whereas acetylation of Lys120 alone tends to induce apoptosis. 96

Many studies have now confirmed that multiple p53 acetylation sites can also affect the prognosis and pathological status of cancer patients. Likewise, patients with high p53 and high acetylation levels had a better prognosis. For example, HCC patients with high levels of p53 Lys120 acetylation have relatively longer OS. 97 Malignant melanoma and HCC patients with high levels of p53 Lys373 acetylation have relatively longer OS and early, lower lymph node metastasis. 98 , 99 HCC, malignant melanoma, and lung cancer patients with high levels of p53 Lys382 acetylation have relatively longer OS and earlier stage and lower lymph node metastasis. 98 , 99 , 100

Ubiquitination and ubiquitin‐like modifications of p53

p53 ubiquitination is the same as acetylation, and it also mainly occurs on lysine residues of p53, including Lys305, Lys319, Lys320, Lys370, Lys372, Lys373, Lys381, Lys382, and Lys386. p53 ubiquitination is mainly mediated by ubiquitinases such as mouse double minute 2 (MDM2), mouse double minute 4 (MDM4), COP1, Pirh2, and Arf‐BP1. 101 , 102 , 103 , 104 However, deubiquitinating enzymes such as USP11 and UCH‐L1 can mediate p53 deubiquitination. 105 , 106 Different levels of ubiquitination have different subsequent effects on p53, for example, high levels of ubiquitination directly mediate the degradation of p53 by the proteasome. When the ubiquitination level is low, it can inhibit the transcriptional activity of p53 by competing with acetyl to bind to the lysine residue of the C‐terminal domain or transfer p53 to the mitochondria, preventing the binding between p53 and target genes in the nucleus. 88 , 107

Ubiquitin‐like proteins are a family of proteins with a structure similar to ubiquitin and a close evolutionary relationship, mainly including small ubiquitin‐like modifier (SUMO), neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), ATG8, ATG12, URM1, UFM1, FAT10, and ISG15. 108 Among them, SUMO and NEDD8 are closely related to p53 modification. 109 The SUMO is a small ubiquitin‐like molecule. 110 The sumoylation of p53 is mainly mediated by specific SUMO‐E3‐ligase such as TOP1 binding arginine/serine‐rich protein (Topor) and protein inhibitor of activated stat. 111 , 112 Compared with ubiquitination, sumoylation of p53 does not promote the degradation of p53 but inhibits the transcriptional activation of p53 on target genes by competing with acetyl for lysine residues in CTR. 113 NEDD8 is a ubiquitin‐like small molecule with a high similarity to ubiquitin. 114 NEDDylation can not only directly inhibit the transcriptional activity of p53, but also prevent the degradation of MDM2, and indirectly promote the ubiquitination of p53 by MDM2. 18

Epigenetic modifications of p53

Epigenetics refers to changes in heritable gene expression or cell phenotype caused by mechanisms that do not alter the DNA sequence. 115 Many macromolecules in organisms undergo chemical modifications that serve crucial functions. 116 Epigenetic modification, which alters gene expression by introducing chemical modifications, is an important form of epigenetic regulation. This includes histone modification, DNA modification, and RNA modification. 117 TP53‐associated H3K9 and H3K14 acetylation promotes TP53 transcription, 118 while monomethylation on H4K20 represses TP53 transcription by inhibiting nucleosome depolymerization. 119 , 120 High levels of H2B ubiquitination are often associated with DNA repair. 121 , 122 High methylation levels in the TP53 promoter region can hinder the binding of transcription factors and inhibit TP53 expression, leading to various cancers. 123 DNA methyltransferase inhibitors such as 5‐aza‐2'‐deoxycytidine can downregulate methylation levels in the TP53 promoter region, facilitating the binding of transcription factors and promoting TP53 expression. 124 Modifications in mRNA can affect its stability, readability, and translation efficiency, 125 and m6A modification in TP53 mRNA can upregulate p53 expression. 126 Nm modification on rRNA 127 and ψ modification on snRNA 128 can indirectly affect p53 expression. Epigenetic regulation complexly and precisely regulates the transcription and translation of the TP53 gene, affecting p53 levels and participating in various disease processes, particularly cancer regulation. 129 However, research on p53‐related epigenetics is still limited and there are many gaps in our understanding of how epigenetic modification affects p53 expression. These include novel histone modifications such as histone sulfation, 130 histone lactylation, 131 and histone lysine benzoylation 132 ; novel DNA methylation modifications such as 3‐methylcytosine (3mC), 133 N4‐methylcytosine (4mC), 134 N6‐methyladenine (6mA), 135 and 7‐methylguanosine (7mG) 136 ; and mRNA modifications such as N1‐methyladenosine (m1A) and N4‐acetylcytidine (ac4C). With the rapid advancement of epigenetic sequencing technology, we can expect many breakthrough discoveries in the field of p53‐related epigenetic modification in the near future.

ACTIVATION AND INACTIVATION OF p53

The activation and inactivation of p53 are precisely regulated by many factors. As shown in Figure 2 , the activation of p53 mainly involves biological mechanisms such as acetylation and phosphorylation, while the inactivation of p53 is closely related to its ubiquitination, ubiquitination, and partial dephosphorylation. 1 , 137 At the same time, various proteins are not only activated by the transcription of p53 but also participate in the regulation of p53 activation or inactivation. 138 p53 and these proteins constitute a complex feedback regulatory network, including Siva1, 139 COP1, 140 Pirh2, 140 cyclin G, 141 ΔNp73, 142 and so on, as well as the classic MDM2. 143

p53 activation‐related factors

ATM protein and ATR both belong to the ataxia telangiectasia (A‐T) family of proteins, but their timing of effects differs. ATM is activated by acetylation of the 60 kDa tat‐interacting protein (TIP60) at DNA double‐strand breaks (DSBs). ATM activates p53, checkpoint kinase 2 (CHK2), and other responsive proteins through phosphorylation, mediating subsequent cell cycle arrest, DNA repair, apoptosis, and other biological processes. 144 ATR is activated when various DNA single‐strand damage occurs, and it plays a similar role to ATM through phosphorylation and activation of p53, checkpoint kinase‐1 (CHK1), and other reactive proteins. 145 CHK1 and CHK2 are cyclin‐dependent kinase (CDK) proteins, which are phosphorylated and activated by ATR and ATM, respectively, thereby acting as phosphokinases to activate p53 and CDC25A and other proteins. 146 , 147

DNA‐PK is a nuclear serine/threonine protein kinase consisting of a catalytic subunit (DNA‐PKcs) and a DNA targeting subunit (Ku). 148 Ku has a high affinity to the end of defective DSB and can recruit DNA‐PKcs to the DSB region, triggering the activation of phosphoinositide 3‐kinase‐related kinase family protein DNA‐PKcs. Subsequently, it phosphorylates many substrates, including DNA‐PKcs itself, XRCC4, and Artemis, and other proteins, including p53, thereby playing a regulatory role in transcription, replication, and DNA repair. 149 , 150

p300/PCB and p300/PCAF are GNAT super‐family proteins, which have the function of acetylating p53, protecting p53 from ubiquitination, thereby promoting the transcriptional activation of p53. 151 , 152 Both TIP60 and MOF are members of the MYST family and were found earlier to have the function of acetylating histone lysine residues. 153 Recent studies have found that TIP60 and MOF have the same ability to acetylate lysine residues on p53, which can promote the transcriptional activation ability of p53 and avoid its ubiquitination. 154 , 155

Multiple p53 negative regulators, including MDM2 and ArfBP1, are inactivated by alternate reading frame (ARF) targeting, which is common during nucleolar stress. 156 The nucleolus is a large organelle without a nuclear membrane and is primarily responsible for the biogenesis of ribosomes. The shape, size, and number of nucleoli are directly related to ribosome biogenesis. 157 When errors in steps of ribosomal biogenesis are sensed by the nucleolus, they trigger nucleolar stress, leading to global changes in nucleolar function and morphology. Nucleolar stress can lead to the inactivation of negative regulatory molecules such as p53, promote p53 stabilization, and then activate cell cycle arrest or apoptosis. 158

The tumor suppressor protein phosphatase and tensin homolog (PTEN) is transcriptionally activated by p53 and has dual‐specificity phosphatase activity, namely protein phosphatase activity and lipid phosphatase activity. 159 PTEN can inhibit the phosphorylation and nuclear translocation of MDM2 by inhibiting the PI3K/AKT signaling pathway. 160 , 161 Activated p53 can induce PTEN to limit the regulation of MDM2 ubiquitination of p53 in the nucleus, thereby greatly increasing the level of p53 in the nucleus. This positive feedback regulation is beneficial to the repair of damage or induces apoptosis of irreversibly damaged cells. 162

p53 inactivation‐related factors

MDM2 exists as a partner of p53 and belongs to the E3 ubiquitin‐ligase class. The C‐terminal zinc finger domain of MDM2 has the ability to ubiquitinate p53 and induce proteasomal degradation of ubiquitinated p53. The N‐terminal domain of MDM2 can also bind to the transcriptional activation domain of p53 by forming a hydrophobic domain and inhibiting its function. 18 , 163 p53 can also target the MDM2 gene and promote MDM2 protein expression. Under normal physiological conditions, a closed‐loop negative feedback regulation is formed between MDM2 and p53, and p53 is maintained at a low level. 18 However, during acute stress, p53 can induce MDM2 to inhibit the expression of various downstream proapoptotic proteins through ubiquitination, providing repair opportunities for damaged cells.

The level of MDM2 is regulated by a variety of proteins, which indirectly affect the activity of p53, including MDM2 itself, SCYL1‐BP1, 164 p14ARF, 165 TRIM8, 166 and so on. In addition, self‐ubiquitination of MDM2 reduces MDM2 levels, which in turn keeps p53 stable. 167 SCYL1‐BP1 can bind to inhibit MDM2 and promote MDM2 autoubiquitination and has a strong inhibitory effect on MDM2. 168 The tumor suppressor gene p14ARF is activated when the proto‐oncogenes C‐MYC, Ras, and E2F1 are activated, and has the ability to inhibit the metastasis of MDM2, thereby inhibiting the ubiquitination of p53 by MDM2. 8 , 169 , 170 , 171 TRIM8 has the ability to bind and inhibit MDM2, can replace p53 and bind to MDM2, and can also degrade MDM2, thereby inhibiting the ubiquitination of p53 by MDM2. 166 MDM2 is also modified by small ubiquitin‐like molecules. For example, NEDD8 can compete with ubiquitin to bind to MDM2 protein, inhibit the self‐ubiquitination process of MDM2, stabilize MDM2, and promote the degradation of p53. 172 SUMO has a zinc finger domain that binds MDM2 and inhibits the ubiquitination of p53 by MDM2. 173 Exogenous factor nutlin‐3 is an exogenous nongenotoxic activator of the p53 pathway, which can indirectly activate the p53 pathway by antagonizing MDM2. The p53 pathway products induced by nutlin‐3 are mainly p21 and PUMA, and play a role in cell cycle arrest and antiangiogenesis. 174 , 175 , 176

MDMX and MDM2 belong to the E3 ubiquitin‐ligase class and have a similar structure to MDM2. 177 MDMX only has the ability to bind and inhibit p53 but lacks the ability to induce the degradation of p53. However, MDMX can bind to MDM2 as a heterodimer to stabilize MDM2, which promotes the ubiquitination of p53 by MDM2. 178 , 179

p53 can target and upregulate COP1, Pirh2, and ArfBP1, and this promotes their ubiquitination and degradation of p53, thereby forming a similar negative feedback regulatory system. 180 , 181 , 182 COP1 also has a mechanism similar to MDM2's self‐ubiquitination. The self‐ubiquitination of COP1 can be activated by ATM phosphorylation, thereby weakening the inhibitory effect on p53 when cells are stressed by external stress. 180 , 183

SIRT1 is a nicotinamide adenine dinucleotide‐dependent sirtuin located upstream of p53, which inhibits the transcriptional activation ability of p53 through the deacetylation of p53. 184 The high expression of SIRT1 plays an important role in the metastasis of various cancers, including prostate cancer (PCa) and ESCC. 185

Leucine zipper‐containing ARF‐binding protein (LZAP) is down‐regulated in various cancer cells. Downregulation of LZAP expression is associated with enhanced invasion, xenograft tumor growth, and angiogenesis. 186 LZAP is generally considered a tumor suppressor, which can inhibit the high level of p53, and mainly plays a tumor suppressor role after p53 mutation or deletion. 187 LZAP is also positively correlated with the function of wild‐type p53‐induced phosphatase 1 (WIP1), which can promote the binding of WIP1 to various substrates. 188 WIP1 belongs to the protein phosphatase 2C (PP2C) family, a mammalian serine/threonine‐specific protein phosphatase. 189 WIP1 can be targeted and activated by p53, and can also dephosphorylate a variety of DNA damage response pathway signaling molecules including p53, which is closely related to the occurrence of cancer. 190 , 191 In general, the phosphorylation at the Ser15 site of p53 can protect itself from being ubiquitinated by binding to MDM2, and WIP1 can remove the phosphorylation at the Ser15 site of p53, thereby restoring the ubiquitination of p53 by MDM2. 192 A recent study shows that the complex formed by p53 and p21 can increase the sensitivity of p53 to WIP1 and MDM2, thereby promoting the dephosphorylation and ubiquitination of p53 to form a negative feedback regulatory loop. 137

REGULATORY MECHANISMS OF p53 On Downstream Genes

As shown in Figure 2 , activated p53 can transcriptionally activate a variety of downstream effector proteins, and play an important role in cell cycle inhibition, DNA damage repair, apoptosis promotion, inhibition of angiogenesis and metastasis, and immune regulation. 40 The functions of the target genes activated by p53 are complex and diverse, and most of them have the function of suppressing tumors, but there are also a small number of target genes that can promote the development of cancer. 193 , 194

Regulation of p53 on cell cycle

Cell cycle checkpoints are important molecular mechanisms in the cell cycle to ensure the quality of DNA replication and chromosome allocation. 195 When abnormal events occur during the cell cycles process, such as DNA damage or DNA replication blockage, the cell cycle checkpoint is activated to interrupt the operation of the cell cycle in time. The cell cycle cannot resume until the cell is repaired. 195 Uncontrolled cell division or dissemination of damaged DNA can lead to genomic instability and tumorigenesis. 196 p53 can induce factors such as p21, GADD45A, and 14‐3‐3σ to arrest the cell cycle, thereby gaining time for DNA repair during damage stress, which can also limit the proliferation of cancer cells.

The p21 protein plays an important role in p53‐mediated cell cycle inhibition. DNA damage or stress signals activate the p53 pathway, transcriptionally activate p21, and finally arrest the cell cycle in the G1/S phase through a series of sequential reactions. 197 , 198 p21 is a CDK inhibitor, a member of the KIP/CIP family, and is often regarded as a negative regulator of the cell cycle. 199 p21 can directly inhibit DNA synthesis by competing with DNA polymerase‐δ and several other proteins involved in DNA synthesis for binding to proliferating cell nuclear antigen (PCNA) through the PCNA binding domain. p21 can also bind to and inhibit the heterodimer of CDK4/6 and cyclin D or the heterodimer of CDK2 and cyclin E through the CDK‐cyclin inhibitory domain, resulting in the inability of the downstream related cyclins to be activated, thereby arresting the cell cycle. 197 , 200 Downregulation of p21 is often associated with uncontrolled tumor growth and worsening symptoms. 201 , 202 Low p21 expression often predicts poor prognosis and more malignant cancer pathology. In NSCLC, patients with low p21 expression have lower 5‐year survival rates. 203 In laryngeal squamous cell carcinoma, low p21 expression is associated with higher cancer pathology grade and increased lymphatic metastasis. 204

When p53 is activated due to DNA damage, the expression of GADD45A increases, which arrests the cell cycle in the G2/M phase and facilitates DNA repair. 205 , 206 GADD45A is a subtype of growth arrest and DNA damage‐inducible 45 protein (GADD45), which plays an important role in cellular stress response and can be upregulated under the induction of various factors including DNA damage. 207 GADD45 exerts the function of cell cycle control mainly by affecting the coordination between CDC2 and cyclin B and arrests the cell cycle in the G2/M period. 208 GADD45A induces DNA demethylation during nucleotide excision repair (NER), fully exposing DNA fragments to lesion‐recognizing factors. 206 GADD45A is downregulated in various tumors such as NSCLC, and its downregulation leads to sustained cell cycling after DNA damage, resulting in increased tumor cell heterogeneity. 209 In oral squamous cell carcinoma (OSCC), low GADD45A expression is associated with poorer OS and predicts lower tumor cell differentiation, higher lymphatic metastasis rates, and increased cancer recurrence. 210

p53 arrests the cell cycle in the G2/M phase by transcriptionally activating 14‐3‐3σ, and plays a role in the response of cells to DNA damage. 211 , 212 14‐3‐3‐σ, also known as stratifin, is mainly found in stratified epithelial cells. 14‐3‐3‐σ, a protein encoded by the SFN gene in humans, is involved in cell cycle checkpoint control after DNA damage. 213 Activated 14‐3‐3‐σ arrests the cell cycle in the G2/M phase by preventing the entry of the mitotic initiation complex CDC2/cyclin B1 complex into the nucleus, providing time for the repair of damaged DNA. 214 While 14‐3‐3‐σ can be promoted by p53, it also has various abilities to regulate the level and activity of p53. 14‐3‐3‐σ can block the biological functions of ubiquitinases MDM2 and COP1, and protect p53 from being degraded by ubiquitination. 215 In addition, 14‐3‐3‐σ can also promote the oligomerization of p53 and enhance its transcriptional activity. 216

Inhibitory mechanism of p53 on angiogenesis

Angiogenesis is the development of new blood vessels from preexisting capillaries or postcapillary veins. Angiogenesis is a complex process of the coordinated action of proangiogenic and inhibitory factors. 217 The occurrence of tumor angiogenesis, on the one hand, is due to the release of angiogenesis factors by tumor cells, which activates vascular endothelial cells, promotes the formation of new blood vessels, and provides nutrients for tumors. On the other hand, it is also due to endothelial cells stimulating the growth of tumor cells by paracrine certain angiogenic factors. 218 p53 can inhibit angiogenesis, reduce tumor blood supply, and inhibit tumor growth and metastasis by inducing factors such as TSP‐1 and BAI1.

p53 induces the expression of thrombospondin‐1 (TSP‐1), which in turn suppresses angiogenesis by inhibiting migration and proliferation of endothelial cells. 219 The angiogenesis inhibitor TSP‐1, which plays a crucial role in tumor growth and metastasis, ultimately alters tumor growth by altering angiogenesis in multiple tumor types. 220 Low TSP‐1 expression in cancer promotes tumor angiogenesis. 221

p53 can inhibit angiogenesis by overexpressing brain angiogenesis inhibitor 1 (BAI1). 222 BAI1, a member of the G protein‐coupled receptor adhesion subfamily, was originally found to be ubiquitously expressed in brain tissue. 223 However, some studies have shown that BAI1 is also expressed in the colon, lung, stomach, kidney, pancreas, and other tissues, and plays an important role in inhibiting angiogenesis. 222 , 224 Overexpression of BAI1 can inhibit tumor growth by inhibiting tumor‐induced angiogenesis. 225 , 226 In glioblastoma (GBM), BAI1 expression is often silenced, promoting tumor angiogenesis. 227 Bladder transitional cell carcinoma patients with low BAI1 expression have more advanced tumor grades and increased cancer cell pleomorphism. 228

p53 regulates energy metabolism in cells

Tumor cells need to consume a lot of energy to maintain growth and invasion. Unlike normal cells, the main way of energy metabolism in tumor cells is glycolysis, so tumor cells need to consume a large amount of glucose to maintain energy consumption. 229 , 230 In addition, the abnormal characteristics of tumor metabolism also include lipid metabolism disorders, abnormal cholesterol metabolism, abnormal protein synthesis, and so on. 231 p53 can regulate cellular energy metabolism, inhibit glycolysis, and promote oxidative phosphorylation by inducing 5' AMP‐activated protein kinase (AMPK), tuberous sclerosis complex 2 (TSC2), PTEN, TP53‐induced glycolysis and apoptosis regulator (TIGAR), and other factors. At the same time, p53 also limits the uptake of energy substances by cancer cells, greatly inhibiting the growth of cancer cells.

Phosphorylation of p53 at Ser15 regulates metabolism by targeting and activating AMPK. 232 AMPK is an intracellular energy sensor widely present in various eukaryotic cell lines. In humans, AMPK regulates glucose and fatty acid metabolism through multiple mechanisms. 233 Under normal physiological conditions, activation of the AMPK signaling pathway can promote catabolism, inhibit anabolism, and increase intracellular ATP levels. 234 When AMPK is activated by p53, it can also promote the phosphorylation and acetylation of p53, forming a positive feedback regulatory loop. 235 , 236 AMPK has a dual regulatory role in tumors, inhibiting cancer cell growth mainly by inhibiting glycolysis and lipid metabolism. 237 , 238 However, some studies have also shown that AMPK has the ability to increase the glucose intake required by tumors and is considered to be closely related to the occurrence and development of various cancers including BrC. 239 There have been several studies targeting AMPK‐targeted therapy in cancer. For example, D‐mannose can activate AMPK, phosphorylate PD‐L1 Ser195 site, lead to abnormal glycosylation and proteasomal degradation of PD‐L1, and improve the sensitivity of triple‐negative BrC patients to immunotherapy and radiotherapy. 240 CPI‐613 reprograms lipid metabolism through AMPK‐ACC signaling to enhance apoptosis in pancreatic cancer cells. 241

TSC2 is transcriptionally regulated by p53, activated by AMPK, inhibits the mTOR signaling pathway, and plays a key role in regulating cellular energy metabolism. 242 , 243 The mammalian target of rapamycin (mTOR), a class of serine/threonine kinases, is an intracellular signaling molecule. 244 Abnormal activation of mTOR signaling can lead to multiple adverse outcomes, including tumor formation, neonatal insulin resistance, and adipogenesis. 245 Inactivating mutations in TSC2 cause hamartomas primarily in multiple organ systems. 246 Loss of TSC2 enhances the sensitivity of hepatoma cell lines to everolimus and AZD8055. 247 Low TSC2 expression leads to hyperactivation of the mTOR pathway and promotes tumor energy metabolism. 248 TSC2 downregulation occurs in various cancers such as NSCLC, and low TSC2 expression predicts poor patient prognosis. 249

p53 can also induce PTEN, thereby inhibiting the energy metabolism of cancer cells, and finally inhibiting tumor growth. 250 PTEN is a protein with both protein and lipid phosphatase activities. 251 PTEN can reduce cellular uptake of glucose and glutamine and increase mitochondrial oxidative phosphorylation by inhibiting PI3K/AKT signaling pathway. At the same time, the inhibited AKT signaling pathway can inhibit the phosphorylation and nuclear translocation of MDM2. 160 , 161 , 252 By inducing PTEN, p53 limits the ubiquitination of nuclear p53 by MDM2, thereby greatly increasing the level of nuclear p53. This positive feedback regulatory loop is conducive to p53 signaling to repair damage or induce apoptosis of irreversibly damaged cells. 253 Low PTEN expression in tumors weakens inhibition of tumor metabolism and promotes tumor development. 254 Clinical studies have shown that low PTEN expression is a significant factor in poor cancer patient prognosis. 255

p53 can play an important role in limiting the growth of cancer cells by inhibiting TIGAR. 256 , 257 TIGAR is a protein containing a functional sequence similar to the 6‐phosphofructo‐2‐kinase/fructose‐2, 6‐biphosphatase domain. 258 TIGAR inhibits glycolysis primarily by hydrolyzing fructose‐1,6‐bisphosphate and fructose‐2,6‐bisphosphate. 259 TIGAR also has the ability to promote the pentose phosphate pathway, which plays an important role in the process of DNA repair and ROS resistance. 260

p53 promotes DNA damage repair

DNA damage repair refers to the phenomenon that DNA molecules in biological cells recover their structure after being damaged by a variety of enzymes, mainly including NER, base excision repair, mismatch repair, and DSB repair. 195 , 261 , 262 , 263 , 264 Timely DNA repair can greatly reduce the chance of cancer. 265 p53 can promote DNA damage repair and inhibit carcinogenesis by inducing factors such as DDB2, SESN1, and SESN2.

DNA damage‐induced high expression of p53 can activate DNA damage‐binding protein 2 (DDB2), repair DNA damage, and inhibit cancer. 266 DDB2 is an essential protein for repairing UV‐damaged DNA, and the heterodimeric protein complex of DDB1/DDB2 is involved in NER. As a smaller subunit of this complex, DDB2 primarily functions in DNA binding. 267 DDB2 expression is downregulated in colorectal cancer (CRC) and other cancers and is closely associated with cancer metastasis. 268 Low DDB2 expression correlates with poor OS in stomach adenocarcinoma (STAD) patients and predicts loss of active immune response to tumors. 269

p53 resists ROS damage by promoting the expression of SESN1, 270 and can also prevent damage and protect cells through SESN2. 271 , 272 The stress‐inducible protein family is a class of conserved antioxidant proteins, which are activated when cells are under oxidative stress and protect cells from ROS through various means, including SESN1, SESN2, and SESN3. Among them, SESN1 and SESN2 are directly regulated by p53. 273 , 274 SESN1 activates the AMPK/PGC‐1α/UCP2 axis and inhibits mitochondrial O2‐ production by forming a complex with AMPK. 270 SESN2 induces cells to promote DNA repair or autophagy by activating the SESN2/AMPK/TSC2 pathway. 275

p53 induces apoptosis

Apoptosis plays an important role in maintaining the stability of the internal environment, and the abnormal regulation of the apoptosis pathway is closely related to the occurrence of tumors. 276 , 277 p53 can promote cell apoptosis and inhibit tumor development by inducing Fas, Bax, NOXA, PUMA, TP53AIP1, AIFM2, IGF‐BP3, and other factors.

DNA damage or stress can induce p53 to transcribe and activate Fas, leading to an increase in the amount of Fas on the cell membrane surface and promoting apoptosis induced by the Fas/FasL pathway. 278 , 279 Fas is considered an apoptotic receptor involved in Fas/FasL pathway‐induced apoptosis. 280 FasL is activated by binding Fas and inducing its trimer formation. After activation, the Fas trimer binds to Fas‐associating via the death domain (FADD), and then FADD continues to recruit caspase 8/10. 281 Fas trimer, FADD, and caspase 8/10 form a death‐inducing signaling complex. In this complex, precaspase 8 self‐cleaves to form active caspase 8, which initiates the downstream caspase cascade reaction and eventually leads to apoptosis. 281 , 282 Low Fas expression results in loss of extrinsic pathway apoptosis signaling in various tumors, leading to malignant cancer progression. 283 , 284 Loss of Fas expression is a major cause of poor prognosis and malignant progression in cancer patients. 285

In addition to participating in death receptor‐mediated apoptosis, p53 can also induce mitochondria‐dependent apoptosis by upregulating the expression level of Bax. 286 , 287 p53 can also promote the expression of various other Bcl‐2 family proteins (such as NOXA, 288 PUMA, 289 etc.), and induce cell apoptosis through the mitochondrial pathway. Siva1 can transmit the apoptotic signal to the cytoplasm at the tail of CD27, a member of the tumor necrosis factor receptor family. And the ectopic expression of Siva1 can also combine with the antiapoptotic protein Bcl‐XL to promote cell apoptosis through the mitochondrial pathway. 290 Siva1 also has the function of ubiquitinating ARF, thereby maintaining the stability of E3 ubiquitinases such as MDM2. p53 can transcriptionally activate Siva1 to play an antiapoptotic role, but at the same time, Siva1 can also induce p53 ubiquitination, forming a negative feedback regulation with p53. 291 Low Siva1 expression enhances cancer cell resistance to apoptotic signals, induces aixib1 survival, and promotes cancer progression. 292 Low Siva1 expression is associated with poorer OS and lower tumor differentiation in cancer patients. 293

Phosphorylation of p53 Ser46 can transcriptionally activate tumor protein p53‐regulated apoptosis‐inducing protein 1 (TP53AIP1), thereby inducing mitochondria‐dependent apoptosis. 294 TP53AIP1 is a protein expressed specifically in the thymus and localized to the mitochondrial membrane. TP53AIP1 induces the subsequent caspase cascade pathway to mediate apoptosis by promoting cytochrome c (Cyt c ) release. 295 Inhibited TP53AIP1 expression impairs the ability to induce apoptosis in cancer cells. Low TP53AIP1 expression in various cancers promotes cancer progression. 296 , 297

Apoptosis‐inducing factor mitochondria‐associated 2 (AIFM2) has significant homology to apoptosis‐inducing factor (AIF) and NADH oxidoreductase but lacks a mitochondrial localization sequence. AIFM2 is transcriptionally activated by p53, binds to DNA in a nonsequence‐specific manner, and induces caspase‐independent apoptosis. 298 A study has also shown that AIFM2 can play an important role in the process of suppressing ferroptosis in a ubiquitin‐dependent manner. 299

Activation of p53 signaling can upregulate the expression of insulin‐like growth factor‐binding protein 3 (IGF‐BP3), thereby promoting apoptosis. 300 IGF‐BP3 is a growth hormone‐dependent IGF binding protein. 301 IGF‐BP3 can bind and stabilize IGF, prevent IGF from being degraded, and promote its transportation in various parts of the body. IGF‐BP3 can also compete with IGF receptors to bind free IGF, and antagonize the proproliferation and antiapoptotic effects of IGF. 302 IGF‐BP3 is expressed at low levels in various cancers such as cervical cancer. Low IGF‐BP3 expression inhibits cell apoptosis and promotes tumor cell proliferation. 303 Low IGF‐BP3 expression often predicts poor patient treatment outcomes. 304 , 305

CLINICAL ADVANCES IN TARGETED p53 Therapy

The p53 signaling pathway plays a crucial role in cancer‐related mutations, providing numerous opportunities for therapeutic intervention. 306 Current approaches to targeting the p53 pathway involve direct regulation of p53 and modulation of p53‐related proteins. However, as a nuclear transcription factor, p53 lacks typical drug target characteristics, presenting significant challenges in drug development and clinical application. 40 While targeted therapy of the p53 pathway is still in its early stages, it holds immense research potential and clinical value and is expected to play a significant role in future cancer treatment. 306

The p53‐targeted drugs

Drugs that target p53 directly work to restore or boost its tumor‐suppressing abilities through a variety of methods such as restoring its conformation, increasing its transcriptional activity, improving its structural stability, and preventing its degradation. Given that p53 mutations are present in over half of all cancers, targeting mutated p53 represents a promising approach. However, research in this area is still in its early stages, with most drugs in preclinical trials and only a few in clinical trials or actual clinical applications (Table 1 ). These include arsenic trioxide (ATO) and COTI‐2 targeting R175H; APR‐246 and APR‐548 targeting R273H; atorvastatin targeting R280K; phenethyl isothiocyanate (PEITC) targeting both R273H and R280K; and PC14586 targeting Y220C. Several other p53‐targeted drugs are still under development, including PhiKan5196, 307 L5, 308 and PK9318 309 targeting Y220C; ADH‐6 targeting R248W 310 ; and Peptide 46 targeting R273H. 311 ATO was found to promote leukocyte apoptosis through multiple mechanisms, including targeting mutant p53, and has been applied in the treatment of acute promyelocytic leukemia. 312 COTI‐2 selectively recognizes and restores mutant p53 through structure‐based design. 313 , 314 APR‐246 is a potential anticancer drug developed by Aprea that restores and activates inactive p53 protein to regain its normal tumor suppressor function. Its precursor, PRIMA, was first identified in 2002 from a library of low‐molecular‐weight compounds targeting p53 mutations. 315 APR‐246 has shown potential therapeutic effects in clinical trials, particularly for tumors harboring p53 mutations. 316 , 317 APR‐548, a new derivative of APR‐246 developed by Aprea, has stronger cell membrane penetration and is believed to have greater anticancer activity. 40 Atorvastatin is a statin drug that lowers cholesterol and lipid levels by inhibiting the enzyme 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase to reduce cholesterol synthesis in the body. However, recent studies have shown that Atorvastatin can also indirectly exert a tumor‐suppressing effect by affecting missense p53. 318 , 319 PEITC is a natural compound extracted from cruciferous plants with broad anticancer properties. 320 , 321 Recent research indicates that PEITC targets multiple mutations such as p53‐R273H and p53‐R280K and reverses the ability of p53 mutant cancer cells. 322 PC14586, an orthotic of p53‐Y220C, has been shown to be tolerable and effective in clinical trials. 323 However, due to the complex dysregulated environment in cancer, it is often difficult to achieve optimal therapeutic effects by targeting p53 alone. 324 , 325 As such, combining p53‐targeted drugs with other commonly used broad‐spectrum anticancer drugs represents a promising approach to cancer treatment. Several p53‐targeted drugs have been combined with common anticancer drugs and entered clinical trials, including acalabrutinib, azacitidine, carboplatin, DDP, cytarabine, dabrafenib, decitabine, pembrolizumab, pegylated liposomal DOX hydrochloride (PLD), and venetoclax.

Drugs targeting p53 signaling‐related proteins

Targeting proteins related to p53 signaling is another viable approach to p53 signaling targeted therapy. This can be achieved through upstream activation of p53 signaling or downstream blocking of abnormal p53 signaling. However, currently only drugs targeting MDM2/MDMX and the downstream metabolic regulatory protein AMPK have entered clinical trials (Table 1 ). These include ALRN‐6924, alrizomadlin, ivaltinostat, idasanutlin, milademetan, navtemadlin, NVP‐CGM097, RO5045337, RO6839921, SAR405838, and siremadlin targeting MDM2/MDMX; and acadesine, ASP4132, HL271, metformin, metformin hydrochloride, and phenformin hydrochloride targeting AMPK.

MDM2/MDMX is a molecular chaperone of p53 that can inhibit its effect through ubiquitination. Targeting MDM2/MDMX is therefore an effective way to enhance p53's anticancer activity. The mechanisms of action of MDM2/MDMX‐targeted drugs currently in clinical trials include inhibiting the interaction between MDM2 and p53, inhibiting MDM2 ubiquitin ligase activity, and downregulating MDM2 expression levels. 326 ALRN‐6924, developed by Aileron Therapeutics, is a peptide inhibitor with dual activity targeting MDM2 and MDMX. It inhibits the interaction between MDM2/MDMX and p53 protein. 327 RG7112, developed by Roche Pharmaceuticals, inhibits the combination of MDM2 and p53 by binding to the p53 binding site on MDM2. 328 RO6839921, developed by Genentech Biotechnology, is an intravenous prodrug of idasanutlin, 329 which selectively antagonizes MDM2 and inhibits its binding to p53. 330 Ivaltinostat indirectly increases MDM2 levels by promoting p53 expression. 331 Milademetan disrupts the interaction between MDM2 and p53. 332 Alrizomadlin inhibits the MDM2–p53 interaction by binding to MDM2. 333 Navtemadlin also inhibits the MDM2–p53 interaction. 334 SAR405838 is a potent and selective inhibitor of the MDM2–p53 interaction. 335 Siremadlin selectively inhibits the p53–MDM2 interaction. 336 NVP‐CGM097 potently and selectively inhibits HDM2, the human homolog of MDM2, and its interaction with p53. 337

AMPK mediates the regulation of metabolism by p53 signaling and inhibits glycolysis and fat metabolism to suppress tumors. Targeting AMPK therefore represents a promising approach to therapy. The mechanisms of action of AMPK‐targeted drugs currently in clinical trials include inhibiting mitochondrial respiration to increase the AMP‐to‐ATP ratio and acting as an AMP analog to indirectly activate AMPK. Acadesine is an adenosine analog that activates AMPK. 338 ASP41322 is a novel mitochondrial complex I inhibitor that increases the AMP‐to‐ATP ratio and indirectly activates AMPK. 339 , 340 Metformin inhibits the mitochondrial respiratory chain in the liver, leading to AMPK activation by increasing the AMP‐to‐ATP ratio. 341 Metformin hydrochloride, phenformin hydrochloride, and HL271 are all biguanide antidiabetic drugs with similar effects to metformin and can activate AMPK. 341 , 342 , 343 However, given AMPK's dual regulatory role in tumors, the value of AMPK‐targeted drugs in cancer requires further exploration through clinical data.

Several other drugs targeting p53 signaling‐related proteins are still under development, including MD‐222, 344 Navtemadlin‐d7, 345 and MX69 346 targeting MDM2; ASP4132, 346 BAY‐3827, 347 and Aldometanib 348 targeting AMPK 339 ; bpV(phen), 349 VO‐OHPic, 350 and Coelonin 351 targeting PTEN; and iFSP1 352 targeting AIFM2.

ONCOGENE TRIAP1: A NOVEL TARGET DOWNSTREAM OF p53

p53 often promotes apoptosis in cells, while its downstream target TRIAP1 mediates its antiapoptotic effect. TRIAP1 reduces mitochondrial membrane permeability, inhibits mitochondrial‐dependent apoptotic pathways, and counteracts the effects of other p53‐related proapoptotic proteins. 365 The transcription of TRIAP1 is activated by p53 signaling, which may contribute to the failure of p53‐targeted therapy.

TRIAP1, also known as a p53‐inducible cell‐survival factor (p53CSV), is an evolutionarily conserved antiapoptotic protein. 366 TRIAP1 is localized to the minus strand of 12q24.31, consists of two exons and one intron (Figures 3 and 4 ), and can be transcribed into two transcripts. Among them, the transcript TRIAP1‐202 (1151 bp) can be translated into protein, while the transcript TRIAP1‐201 (1153 bp) does not contain an open reading frame.

TRIAP1 is a homolog of MDM35, the sequence and structure of the two are similar, but the N‐terminus of MDM35 also has a short α‐helix, and the C‐terminus is more flexible than TRIAP1 (Figure 3 ). 367 Similar to MDM35, 368 TRIAP1 can form a heterodimer with protein of relevant evolutionary and lymphoid interest (PRELI) protein and play the role of transporting phospholipids in the mitochondrial intermembrane space. 369 TRIAP1 can inhibit mitochondrial cleavage and the activation of downstream apoptotic protease activating factor‐1 (APAF1)/apoptosome, and play an antiapoptotic effect. 370 Experiments have shown that the expression level of TRIAP1 is generally elevated in 9 types of cancers (Table 2 ).

The molecular mechanism of TRIAP1

As shown in Figure 4 , The expression of TRIAP1 is regulated by multiple mechanisms, including the regulation of TRIAP1 transcription by p53 protein 41 and the targeted repression of TRIAP1 by 12 microRNAs (miRNAs). As shown in Figure 5 , TRIAP1 can form a heterodimeric complex with PRELI‐like family proteins and inhibit mitochondrial lysis, inhibit the activation of apoptotic peptidase activating factor 1 (APAF1)/apoptosome, and then inhibit apoptosis. 41

A functional p53‐binding sequence (p53BS) is present in exon 1 of TRIAP1 (Figure S1 ). TRIAP1 expression is dependent on p53 protein, and it is hardly expressed in p53 −/− HCT116 cells. Phosphorylation modifications at different sites of p53 protein also have different effects on the expression of TRIAP1. 41 Among them, p53 Ser15 phosphorylation can be induced when DNA is slightly damaged, thereby promoting the expression of TRIAP1, which in turn induces cell survival and damaged DNA repair. When DNA is severely damaged, p53 Ser46 phosphorylation can be induced, which will reduce the expression level of TRIAP1 and induce apoptosis. 41 The expression of TRIAP1 is regulated by a variety of ncRNAs at the posttranscriptional level, including miRNAs, circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs) (Table S1 ). miRNA can bind to the 3'‐UTR of target gene messenger RNA (mRNA), thereby inducing the degradation of target mRNA or inhibiting its expression. 387 Competing endogenous RNAs (ceRNAs), including lncRNAs and circRNAs, can act as molecular sponges for miRNAs and competitively inhibit the targeting of miRNAs to protein‐coding genes. 388 To date, 12 miRNAs have been reported to target TRIAP1, including miR‐18a in epithelial ovarian cancer, 380 miR‐107 in BrC, 379 gastric cancer (GC), 43 NSCLC, 386 and OSCC, 374 miR‐125a‐5p in HCC 373 and thyroid cancer (TC), 375 miR‐137 in osteosarcoma (SaOS), 376 miR‐203 in PCa, 382 miR‐320b in nasopharyngeal carcinoma (NPC), 385 miR‐506 in PCa, 381 miR‐539 in SaOS, 370 and miR‐1301 in SaOS, 377 and miR‐125b‐5p, 389 miR‐320d, 390 and miR‐770‐5p 391 , 392 in noncancerous disease. Three of these miRNAs are also involved in ceRNA axes, including the circPVT1/miR‐137/TRIAP1 in SaOS, 376 MFI2‐AS1/miR‐125a‐5p/TRIAP1 in TC, 375 and PCGEM1/miR‐506/TRIAP1 in PCa. 381 Bioinformatics analysis revealed a strong correlation between the expression of TRIAP1 and TP53 gene mutation and RNA m6A modification (see Supplementary Materials ).

PRELI family proteins can form a mitochondrial intermembrane complex with TRIAP1. 393 , 394 Three proteins in the PRELI family (including PRELID1, PRELID3A, and PRELID3B) have PRELI‐like domains, which are involved in the regulation of phospholipid transport in mitochondria, 395 and are closely related to a variety of malignant tumors. 396 Phosphatidic acid (PA), the precursor phospholipid of cardiolipin (CL), is transferred to the inner mitochondrial membrane by the TRIAP1/PRELI complex and converted to CL by CL synthase. 397 Deletion of TRIAP1 or PRELI reduces the CL content in the mitochondrial membrane, which in turn promotes mitochondrial lysis and Cyt c release, ultimately leading to apoptosis. 365 TRIAP1 can inhibit the expression of the proapoptotic protein Bax, or interact with APAF1 and HSP70, inhibit the formation of downstream apoptosomes, and reduce the level of caspase activation, ultimately inhibiting apoptosis. 392 Bcl‐2 family‐related proteins are a class of apoptosis regulators, among which Bax overexpression promotes the release of Cyt c from mitochondria. When Bcl‐2 is overexpressed, it can form a heterodimer with Bax and inhibit the effect of Bax on promoting the release of Cyt c from mitochondria. 398 TRIAP1 can increase the level of Bcl‐2 and inhibit the level of Bax in cells, thereby inhibiting the release of Cyt c in mitochondria, inhibiting the activation of AFAF1/apoptosome, and inducing cell survival. 392 Heat shock protein (HSP) is a large protein with a highly conserved sequence involved in the folding and maturation of other proteins. 399 APAF1/apoptosome plays a key role in embryonic development and mitochondria‐dependent apoptosis. 400 Among them, HSP70 can bind to APAF1 and inhibit its activity, while TRIAP1 can interact with HSP70 and/or APAF1, thereby inhibiting the activation of APAF1, 41 and inhibiting the activation of the apoptosome, reducing caspase activity and inducing cell survival. 372 , 389

The dysregulated TRIAP in cancer

The inhibition of the apoptosis pathway is an important reason for the occurrence and development of cancer. 401 As shown in Table 2 , many studies have so far confirmed that TRIAP1 is highly expressed in cancers of various human systems and plays a role in promoting cancer. When TRIAP1 expression is inhibited, the malignant phenotype of cancer cells is also inhibited.

In the blood system, multiple myeloma (MM) is characterized by the transformation of plasma cells in the bone marrow into cancer cells and clonal proliferation. 402 TRIAP1 is highly expressed in MM, 371 and overexpressed TRIAP1 can inhibit the activation of APAF1/apoptosome, thereby inhibiting cancer cell apoptosis, leading to cancer progression. 372

In the digestive system, GC is cancer that occurs in the mucosa of the stomach. 403 Overexpressed miR‐107 inhibited the proliferation, invasion, and metastasis of GC cell line (NCI‐N87) by targeting TRIAP1, and promoted apoptosis. Similarly, low expression of TRIAP1 inhibited tumor progression in NCI‐N87 cell xenograft in BALB/c athymic nude mice. 43 HCC is the most common type of chronic liver cancer in adults. 404 Overexpressed miR‐125a‐5p targeting TRIAP1 downregulates the viability of HCC cell line PLC/PRF/5, inhibits cell invasion and migration, and promotes apoptosis. 373 OSCC is a type of cancer that produces lesions in the histiocytic and squamous cells of the oral cavity. 405 In OSCC, the highly expressed miR‐107 targeted the inhibition of TRIAP1, which in turn inhibited the proliferation, invasion, and migration of OSCC cell lines (CAL‐27 and OSC‐4). 374

In endocrine system neoplasm, TC is a malignant tumor of the thyroid tissue that occurs in the Endocrine system. 406 In TC, the highly expressed MFI2‐AS1 upregulated the expression level of TRIAP1 by competitively inhibiting miR‐125a‐5p, inhibited the apoptosis of cancer cells, and promoted the proliferation, invasion, and metastasis of cancer cells. 375

In the motor system, SaOS is a malignant tumor that can arise in all bone tissues and is characterized by rapid development and early metastasis. 407 In SaOS, highly expressed circPVT1 upregulates the expression level of TRIAP1 by competitively inhibiting miR‐137 and hinders the apoptosis of cancer cells (KHOS and U2OS), ultimately promoting the malignant progression of cancer. 376 Meanwhile, the circPVT1/miR‐137/TRIAP1 axis promoted tumor growth in xenografted BALB/c nude mice. 376 Overexpressed miR‐539 370 and miR‐1301 377 can suppress the malignant phenotype of SaOS cell lines and promote cancer cell apoptosis by targeting TRIAP1. Meanwhile, low expression of TRIAP1 can also inhibit tumor growth and metastasis in xenografted BALB/nude mice. 370

In the reproductive system, BrC is cancer derived from breast tissue. 408 In BrC, highly expressed miR‐107 targets TRIAP1 in the BrC cell line (MCF‐7), leading to down‐regulation of cancer cell MCF‐7 viability and promoting cancer cell apoptosis. 379 Overexpressed TRIAP1 also blocked the activation of APAF1/apoptosome and promoted the malignant phenotype of BrC cell lines (CAL51 and MCF7). 378 Ovarian cancer (OC) is cancer that originates in the ovaries of women. 409 In OC, overexpressed TRIAP1 inhibits apoptosis of cancer cell SKOV3 by inhibiting the activation of APAF1/apoptosome. 44 Overexpressed miR‐18a targets and inhibits TRIAP1, thereby inhibiting the cell cycle and proliferation of cancer cells (A2780cp and A2780s) and promoting cancer cell apoptosis. Meanwhile, low expression of TRIAP1 inhibited tumor growth in xenografted BALB/c nude mice. 380 PCa is a malignant tumor originating from the male prostate. 410 In PCa, overexpressed PCGEM1 competitively represses miR‐506, which in turn leads to the upregulation of TRIAP1. 381 In PCa, overexpressed PCGEM1 or TRIAP1 can inhibit apoptosis and promote the malignant phenotype of cancer cells (PC‐3 and C4‐2B) 383 and promote tumor growth in xenografted BALB/c nude mice. 381 Overexpressed miR‐203 can target and inhibit TRIAP1, thereby promoting apoptosis of cancer cells (RasB1). Meanwhile, low expression of TRIAP1 inhibited tumor growth and metastasis in xenografted male nude mice. 382

In the respiratory system, NPC is cancer that develops in the upper throat or nasopharyngeal cavity. 411 In NPC, overexpressed miR‐320b targets and inhibits TRIAP1, promotes mitochondrial fragmentation and Cyt c release, which in turn inhibits the proliferation of cancer cells (CNE‐2 and SUNE‐1) and promotes cancer cell apoptosis. 385 Meanwhile, low expression of TRIAP1 inhibits tumorigenesis in xenografted BALB/c nude mice. 385 NSCLC is any type of lung cancer of epithelial origin other than small‐cell lung carcinoma. 412 In NSCLC, overexpressed miR‐107 targets TRIAP1, which in turn inhibits proliferation and promotes apoptosis in an NSCLC cell line (A549). 386

Prognostic value of TRIAP1

In NPC, NSCLC, and penile carcinoma (PeCa), overexpressed TRIAP1 is a high‐risk factor for patient survival. Among them, patients with NPC and NSCLC overexpressing TRAIP1 had shorter OS 366 , 385 and DFS. 385 PeCa patients overexpressing TRIAP1 have higher tumor histological grades and shorter local RFS and thus can be used as a predictor of cancer recurrence. 384

In TCGA data, high expression of TRIAP1 was a high‐risk factor for cancer patient survival, and it was significantly associated with poorer OS in 7 tumors and poorer disease‐specific survival (DSS) in eight tumors (hazard ratio (HR) > 1 and p < 0.05). This is consistent with the results mentioned above that the expression of TRIAP1 in these cancer tissues is higher than that in the corresponding normal tissues, indicating that TRIAP1 can be used as a marker for the diagnosis and prognosis of these cancers. (See Supplementary Materials and Figure S2A for details.)

We also calculated the correlation of TRIAP1 with the tumor microenvironment and tumor stemness. The results also showed that in most cancers, TRIAP1 was negatively correlated with ESTIMATE score 413 and positively correlated with cancer‐associated fibroblast (CAF) hallmarks 414 and tumor stemness 415 (see Supplementary Materials and Figures S2B and S2C ). Low activity of antitumor immune cells, high activity of CAFs, and high tumor stemness may be the reasons for malignant tumor progression and poor prognosis in patients with high TRIAP1 expression.

Potential cancer therapy targeting TRIAP1

The drug resistance of tumor cells is one of the important reasons for the failure of chemotherapy and radiotherapy. TRIAP1 plays an important role in promoting tumor resistance to treatment. TRIAP1 inhibits cell apoptosis by blocking the mitochondria‐dependent apoptotic pathways and induces tolerance. As shown in Table S2 , TRIAP1 is more expressed in multidrug‐resistant cancer cell lines (DOX, DDP, TAM, and VP‐16) than in corresponding sensitive cell lines. As shown in Figure 6A , TRIAP1 can promote the resistance of cancer cells to radiation and various anticancer drugs, including DOX, DDP, tyrosine kinase inhibitor (TKI), TAM, and taxol (PTX).

DOX is an antitumor antibiotic, which can inhibit the synthesis of RNA and DNA. DOX has a broad antitumor spectrum and has an effect on a variety of tumors, and has a killing effect on tumor cells in various growth cycles. 416 In BrC 378 and SaOS, 376 TRIAP1 was significantly upregulated in DOX‐resistant cell lines than in corresponding DOX‐sensitive cell lines. Low and moderate doses of DOX promote TRIAP1 expression and induce DOX resistance in BrC cell lines (CAL51 and MCF7). 378 However, high doses of DOX inhibited TRIAP1 expression and induced cell death. 378 Overexpressed circPVT1 increased the expression of TRIAP1 by competitively inhibiting miR‐137, inhibited caspase 3 cleavage maturation, and finally induced DOX‐resistance in SaOS cell lines (KHOS and U2OS). 376 Epirubicin (EPI), an antibiotic antineoplastic drug, is an isomer of DOX that intercalates directly between DNA nucleobases and interferes with the transcription process. 417 In SaOS, EPI can promote the expression of miR‐1301 and hinder the expression level of TRIAP1, thereby inhibiting the proliferation of U2OS and SAOS‐2 cell lines, promoting apoptosis, and exerting therapeutic effects. 377

DDP, also known as cis‐dichlorodiammine platinum, is a platinum‐containing anticancer drug, which has a clinical curative effect on various solid tumors such as ovarian cancer, prostate cancer, and testicular cancer. 418 In OC, the expression level of TRIAP1 was significantly higher in the DDP‐resistant SKOV3 cell line than in the DDP‐sensitive SKOV3 cell line. 44 Highly expressed TRIAP1 induces DDP resistance from SKOV3 in vitro and in vivo by inhibiting mitochondrial cleavage and apoptosis. 44 TKIs are effective targeted drugs for the treatment of various malignant tumors. TKIs can competitively bind ATP at the catalytic binding site of tyrosine kinases and inhibit tumor activity by inhibiting the phosphorylation process. 419 In PCa, EGFR/RAS signaling upregulates TRIAP1 expression by inhibiting the miR‐203 expression and ultimately induces resistance to TKIs in a PCa cell line (RasB1). 382 TAM is a selective estrogen receptor modulator that blocks estrogenic action in breast cells and activates estrogenic activity in other cells such as bone, liver, and uterine cells. Therefore, TAM may play a role in the treatment of cancer. 420 Etoposide (VP‐16) is a commonly used antitumor chemotherapeutic drug that inhibits DNA replication, thereby inhibiting the cell cycle of cancer cells, and promoting cancer cell apoptosis and autophagy. 421 In BrC, the expression level of TRIAP1 was significantly higher in TAM and VP‐16 resistant MCF7 cell lines than in sensitive MCF7 cell lines. 378 PTX, a diterpene alkaloid compound with anticancer activity, is widely used in the treatment of breast, ovarian, and some head and neck, and lung cancers. 422 In BrC, miR‐107 can inhibit TRIAP1 expression, sensitize the MCF‐7 cell line to PTX, and induce apoptosis. 379

Radiation, consisting of the flow of atomic and subatomic particles and waves, including ionizing radiation, ultraviolet rays, and X‐rays, can be used in the treatment of various cancers. 423 TRIAP1 enhances radiation resistance in NSCLC cell lines (A549 and H460), 366 PCa cell lines (PC3), and CRC cell lines (HCT116). 41 Radioresistant CAFs can promote radioresistance in PC3 xenograft tumors by secreting TRIAP1. 383 At the same time, irradiation can upregulate the expression of TRIAP1 in NSCLC cell lines (A549 and H460), mediate the upregulation of various antioxidant proteins after irradiation, and finally induce ionizing radiation resistance. 366

Therefore, therapeutic regimens targeting TRIAP1 may play an effective therapeutic role. We utilized Autodock Vina software (version 1.1.2, Linux) to perform batch molecular docking of TRIAP1 with 1438 FDA‐approved drugs to screen its targeted drugs. As shown in Table S3 , 36 drugs were screened that could bind strongly to TRIAP1 (score < −7). As shown in Figure 6B , Ergotamine (score = −8.1) and Venetoclax (score = −8.5) could tightly bind to the surface of TRIAP1. This suggests that Ergotamine and Venetoclax are likely to be potential targeted inhibitors of TRIAP1.

Discussion

TRIAP1 is located at 12q24.31 and consists of two exons and one intron. TRIAP1 is a homolog of the yeast protein MDM35 with a similar structure and function. TRIAP1/PRELI heterodimers can transport phospholipids in the mitochondrial intermembrane space. TRIAP1 can exert an antiapoptotic effect by blocking mitochondria‐dependent apoptotic pathways.

TRIAP1 expression is strictly dependent on p53. The binding of p53 to the upstream sequence of TRIAP1 and the phosphorylation of p53 at different sites can have different effects on the expression of TRIAP1. In addition, the translation process of TRIAP1 was also inhibited by 12 miRNAs. Three ceRNAs can upregulate the expression level of TRIAP1 by competitively inhibiting miRNA. TRIAP1 was significantly positively correlated with the expression of most RNA‐modifying genes, indicating that TRIAP1 expression may be subjected to a large number of RNA modifications. But this still needs to be confirmed by experiments, which may be an important research direction for TRIAP1 expression regulation in the future.

TRIAP1 is highly expressed as an oncogene in most tumors and is only lowly expressed in PCPG. TRIAP1 plays an important role in the occurrence and development of cancer by inhibiting the apoptosis of cancer cells. Likewise, in most cancers, high expression of TRIAP1 is a high‐risk factor for patient prognosis. The expression level of TRIAP1 in cancer was significantly inversely correlated with ESTIMATE scores and positively correlated with CAFs activation status and tumor stemness. This may be the reason for the poor prognosis of patients with high expression of TRIAP1.

Interestingly, TRIAP1 was lowly expressed in PCPG and was hardly modified by RNA methylation. In PCPG, the TRIAP1 expression level was significantly positively correlated with ESTIMATE scores, and significantly negatively correlated with tumor stemness. Therefore, we speculate that TRIAP1 is subject to a unique regulatory mechanism in PCPG and thus plays different roles. Again, this still needs to be supported by experimental data. Elucidating the reason why TRIAP1 is different in PCPG from most other cancers may lead to a new understanding of TRIAP1 function.

Although there have been studies related to TRIAP1 and drug therapy, there is still no research and development of TRIAP1‐targeting drugs. As a tumor suppressor gene, TP53 can inhibit the proliferation of cancer cells and induce their apoptosis. However, TRIAP1 expression was significantly positively correlated with TP53 and mediated the antiapoptotic effect of TP53. Due to the particularity of the regulatory mechanism of TRIAP1 expression, high expression of TRIAP1 is likely to be the cause of drug resistance in most TP53‐targeted treatments. For example, sublethal doses of drugs may lead to phosphorylation of p53 Ser15, upregulate TRIAP1 expression, and induce cell resistance. Therefore, the drug treatment regimens around TRIAP1 and the treatment methods to avoid or reduce the development of drug resistance still need to be further studied. The development of TRIAP1‐targeted drugs is also imminent, which is also the focus and difficulty of future TRIAP1‐related research.

CONCLUSIONS AND PERSPECTIVE

p53 is encoded by the TP53 gene located at 17p13.1 and has 7 functional domains and 12 spliced isoforms. TP53 is the gene with the highest mutation frequency in tumors. The DBD missense mutation of TP53 will lead to abnormal function or inactivation of p53, which usually promotes tumorigenesis and development. The p53 pathway is a signaling pathway that receives and prevents information on cellular metabolic disorders and genetic material damage and can be activated when receiving stress signals. p53 is usually activated in the form of phosphorylation or acetylation, and inactivated in the form of ubiquitination or ubiquitin‐like. High levels of phosphorylated or acetylated p53 often predict better prognosis and survival in patients. Activated p53 forms a tetramer, binds to a variety of target genes, and promotes their transcription, thereby inhibiting cell carcinogenesis through various pathways, including blocking the cell cycle, inhibiting angiogenesis, regulating metabolism, promoting DNA damage repair, inducing cell apoptosis, and so on.

TRIAP1 is a novel p53‐dependent antiapoptotic gene that is highly expressed in various cancers. TRIAP1 is tightly regulated by p53 and mediates the antiapoptotic activity of p53. The expression of TRIAP1 is also subject to multiple epigenetic regulations, including RNA modification, and targeted binding of noncoding RNAs. Overexpression of TRIAP1 is a high‐risk factor affecting patient survival and is one of the reasons why many cancer cells develop drug resistance. With the progress of related treatment research and the development of targeted drugs, TRIAP1 is expected to play a vital role in clinical cancer treatment.

Although targeted therapy based on p53 signaling has been studied for decades, few drugs have been put into clinical trials or practical applications. Achieving targeted therapy of p53 signaling will be a disruptive achievement in cancer treatment research. There are various reasons why p53 signaling is currently difficult to target for therapy. For example, it may be due to differences in p53 mutation sites between different patients, or it may be the impact of differences in the expression of other genes on p53 signaling. There are still many gaps in the research on the p53 signaling pathway, such as the role of different mutations on p53 in different cancers, the phosphorylation or acetylation of different sites of p53 on the activation of different downstream factors, and so on. In the future, we need to know more about the impact of different site modifications on p53, in order to further explore the abnormal site of p53 signal in patients, so as to make a more precise treatment plan.

p53 can play a tumor suppressor role by activating multiple downstream genes, but some genes that are transcriptionally activated by p53 have tumor‐promoting activity, such as TRIAP1 and so on. TRIAP1 is a rare p53‐dependent oncogene that mediates the antiapoptotic activity of p53. Targeting TRIAP1, which is aberrantly expressed in cancer, is likely to be an effective cancer treatment option and has the potential to address resistance to p53 therapy. However, there are still many unknowns about the regulation of TRIAP1. In the future, relevant research needs to be carried out, such as the effect of phosphorylation at different sites of p53 on the expression of TRIAP1, the effect of other modifications of p53 on TRIAP1, whether TRIAP1 has feedback regulation on p53, and so on.

Therefore, ascertaining the p53 signaling pathway and continuously exploring new molecular mechanisms in p53 signaling is the research basis for targeted therapy. Individually differentiated treatment for p53 abnormalities in different patients will greatly improve the prognosis, survival time, and quality of life of cancer patients.

AUTHOR CONTRIBUTION

J. S., Q. W., Y. M., W. G., and S. D. collected and analyzed the literature, drafted the figures, and wrote the paper; S. D. and W. G. conceived and gave the final approval of the submitted version. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that there are no competing interests.

ETHICS STATEMENT

Not applicable.

Supporting information

Supporting Information

Click here for additional data file.

ACKNOWLEDGMENTS

The authors would like to thank PubMed, NCBI, RCSB PDB, and Genome Browser databases for the valuable information. Figure 5 and part of the materials in the graphic abstract and Figures 2 and 4 were created by BioRender (biorender.com).

DATA AVAILABILITY STATEMENT

Not applicable.

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