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HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies.

The hypoxic microenvironment is an essential characteristic of most malignant tumors. Notably, hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulatory factor of cellular adaptation to hypoxia, and many critical pathways are correlated with the biological activity of organisms via HIF-1α. In the intra-tumoral hypoxic environment, HIF-1α is highly expressed and contributes to the malignant progression of tumors, which in turn results in a poor prognosis in patients. Recently, it has been indicated that HIF-1α involves in various critical processes of life events and tumor development via r

Epimutational profile of hematologic malignancies as attractive target for new epigenetic therapies.

In recent years, recurrent somatic mutations in epigenetic regulators have been identified in patients with hematological malignancies. Furthermore, chromosomal translocations in which the fusion protein partners are themselves epigenetic regulators or where epigenetic regulators are recruited/targeted by oncogenic fusion proteins have also been described. Evidence has accumulated showing that "epigenetic drugs" are likely to provide clinical benefits in several hematological malignancies, granting their approval for the treatment of myelodysplastic syndromes and cutaneous T-cell lymphomas. A

ATGL sensitizes hepatocellular carcinoma cells to genotoxic drugs by modulating p53 acetylation/phosphorylation status.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases. Few therapeutic options are available for HCC patients due to intrinsic drug resistance or the low efficacy of conventional chemotherapeutic drugs, including genotoxic agents. We previously demonstrated that adipose triglyceride lipase (ATGL) is downregulated in HCC and shows anti-neoplastic activity by affecting sensitivity to different therapeutic approaches. On the basis of this evidence, we assessed the contribution of ATGL activity to the modulation of the DNA damage response induced by genotoxic drugs. W

Mechanisms of Cancer Resistance to Immunotherapy.

Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor

Immunotherapy of Hematological Malignancies of Human B-Cell Origin with CD19 CAR T Lymphocytes.

Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Mara

A comprehensive prognostic score for head and neck squamous cancer driver genes and phenotype traits.

BackgroundHead and neck squamous cancer (HNSCC) presents variable phenotype and progression features. Clinically applicable, high-accuracy multifactorial prognostic models for HNSCC survival outcomes are warranted and an active area of research. This study aimed to construct a comprehensive prognostic tool for HNSCC overall survival by integrating cancer driver genes with tumor clinical and phenotype information.MethodsKey overall survival-related cancer driver genes were screened from among main effector and reciprocal gene pairs using TCGA data using univariate Cox proportional hazard regres

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… activating factor acetylhydrolase 1b catalytic subunit 2 MYC proto-oncogene, bHLH transcription factor SET nuclear proto-oncogene Death domain associated protein FMS related tyrosine kinase 3 FMS related tyrosine kinase 3 ligand C–C motif chemokine receptor 7 Cluster of differentiation 79A Lysine acetyltransferase … Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018;560(7717):253–257. doi: 10.1038/s41586-018-0387-5. 44. Huang SN, Li GS, Zhou XG, Chen XY, Yao YX, Zhang XG, et al. …

Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release.

BACKGROUND: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia. METHODS: The CT26 and LLC tumor cells were subcutaneously in

Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

Gene editing and CRISPR in the clinic: current and future perspectives.

Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases whic

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

The integration of liquid biopsy with epigenetic markers offers significant potential for early lung cancer detection and personalized treatment. Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA changes, often precede genetic mutations and are critical in cancer progression. In this study, we explore how liquid biopsy, combined with epigenetic markers, can provide early detection of lung cancer, potentially predicting onset up to 4 years before clinical diagnosis. We discuss the challenges of targeting epigenetic regulators, which could disrupt cellul

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… Histone acetylation occurs through the addition of acetyl groups to specific lysine residues by histone acetyltransferases (HATs), and acetylation leads to the opening of chromatin structures, which enables active gene transcription. … The NLRP11 protein bridges the histone lysine acetyltransferase KAT7 to acetylate vimentin in the early stage of lung adenocarcinoma . …

Advances of HDAC inhibitors in tumor therapy: potential applications through immune modulation.

Histone deacetylase inhibitors (HDAC inhibitors, HDACi) have garnered considerable attention due to their potential in treating various types of malignant tumors. Histone deacetylases (HDACs) not only influence chromatin structure and gene transcription by regulating histone acetylation status but also acetylate various non-histone proteins. They are widely involved in several key biological processes, such as cell cycle regulation, apoptosis induction, and immune responses. HDACi exert their effects by inhibiting HDAC activity; however, these effects are highly concentration-dependent and non

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… Histone acetyltransferases(HATs) add an acetyl group to histone lysine residues. The positively charged acetyl group can neutralize the charge interaction between DNA and histones, thereby loosening the chromatin structure and facilitating transcription. … Histone acetyltransferases (HATs) add acetyl groups, indicated as “Ac,” promoting an open status. Histone deacetylases (HDACs) remove these groups, leading to a closed status. HDAC inhibitors block this removal, maintaining open chromatin and promoting transcription. …

Perturbing Enhancer Activity in Cancer Therapy.

Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation.

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… Histone acetyltransferases (HATs), such as p300 and CREB-binding protein (CBP), transfer an acetyl group from acetyl-CoA to histone tails [ 91 ]. … Structure and ligand of a histone acetyltransferase bromodomain Nature 1999 399 491 496 10.1038/20974 10365964 80. Filippakopoulos P. Knapp S. Targeting bromodomains: Epigenetic readers of lysine acetylation Nat. Rev. Drug Discov. 2014 13 337 356 10.1038/nrd4286 24751816 81. Picaud S. Wells C. …

Lost in transcription: molecular mechanisms that control HIV latency.

Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover,

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… In addition to the equilibrium between histone acetyltransferases (HATs) and histone deacetylases (HDACs), several other components are also involved in their recruitment to the viral promoter. … Since an acetylation-defective mutant CDK9 (K44R) and CDK9 isolated from cells over-expressing HDAC1 or HDAC3 are kinase deficient, the acetylation of CDK9 might be important for its kinase activity. p300 or members of the GCN5-related N-acetyltransferase (GNAT) family (GCN5 and PCAF) mediate this CDK9 …

CRISPR/Cas9: A revolutionary genome editing tool for human cancers treatment.

Cancer is a genetic disease stemming from genetic and epigenetic mutations and is the second most common cause of death across the globe. Clustered regularly interspaced short palindromic repeats (CRISPR) is an emerging gene-editing tool, acting as a defense system in bacteria and archaea. CRISPR/Cas9 technology holds immense potential in cancer diagnosis and treatment and has been utilized to develop cancer disease models such as medulloblastoma and glioblastoma mice models. In diagnostics, CRISPR can be used to quickly and efficiently detect genes involved in various cancer development, prol

Collateral Victim or Rescue Worker?-The Role of Histone Methyltransferases in DNA Damage Repair and Their Targeting for Therapeutic Opportunities in Cancer.

Disrupted DNA damage signaling greatly threatens cell integrity and plays significant roles in cancer. With recent advances in understanding the human genome and gene regulation in the context of DNA damage, chromatin biology, specifically biology of histone post-translational modifications (PTMs), has emerged as a popular field of study with great promise for cancer therapeutics. Here, we discuss how key histone methylation pathways contribute to DNA damage repair and impact tumorigenesis within this context, as well as the potential for their targeting as part of therapeutic strategies in ca

Mechanism and therapeutic potential of traditional Chinese medicine extracts in sepsis.

Sepsis is a complex syndrome characterized by multi-organ dysfunction, due to the presence of harmful microorganisms in blood which could cause mortality. Complications associated with sepsis involve multiple organ dysfunction. The pathogenesis of sepsis remains intricate, with limited treatment options and high mortality rates. Traditional Chinese medicine (TCM) has consistently demonstrated to have a potential on various disease management. Its complements include reduction of oxidative stress, inhibiting inflammatory pathways, regulating immune responses, and improving microcirculation. Tra

Harnessing Epigenetic Mechanisms to Overcome Immune Evasion in Cancer: The Current Strategies and Future Directions.

Combining epigenetic alterations with cancer immunotherapy offers a promising approach to improve therapeutic outcomes by targeting the complex biology of tumors. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) play a dual role in maintaining immune homeostasis and promoting cancer progression. Changes like hypomethylation in tumor cells can contribute to immune evasion and treatment resistance. Advances in epigenetic tools, particularly clustered regularly interspaced short palindromic repeat (CRISPR) and their associated protein (Cas9)-based

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… Targeting DNMT3A restores normal methylation patterns and improves antigen presentation, and modulating histone acetyltransferases (HATs), histone deacetylases (HDACs), sirtuins, lysine-specific demethylase 1 (LSD1), polycomb repressive complex 1 (PRC1), and ten-eleven translocation (TET) enzymes can …

SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy.

Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was admin

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… Chromatin acetylation is controlled by the opposite effects of two families of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). …

The epigenetic revolution in hematology: from benchside breakthroughs to clinical transformations.

The field of hematology has experienced a substantial evolution with the acknowledgment of epigenetic processes as essential factors in the development of hematological malignancies. This review article examines the influence of epigenetic alterations, namely DNA methylation and histone modifications, on the onset and advancement of conditions such as acute myeloid leukemia and myelodysplastic syndromes. We discuss how these epigenetic modifications lead to the deregulation of gene expression, eventually promoting leukemogenesis. The emergence of epigenetic therapies, such as DNA methyltransfe

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… For example, histone methyltransferases (HMTs) such as EZH2 and histone acetyltransferases (HATs) such as CBP and p300 add methyl or acetyl groups to lysines or arginines on histones [ 26 ]. … Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510–7. 142. Bester AC, et al. An integrated genome-wide CRISPRa approach to functionalize lncRNAs in drug resistance. Cell. 2018;173(3):649-664.e20. 143. …

Тематический анализ прогноза, диагностики и терапии циркулирующих биомаркеров миРНА в борцезомибно-стойких миеломах.

ЦЕЛЬ: Растущий спрос на точную медицину стимулировал молекулярные диагностические исследования, с тем чтобы подчеркнуть полезность микроРНК в качестве важных биомаркеров. В недавних исследованиях подчеркивается роль МИРНА как перспективных, диагностических и терапевтических биомаркеров в управлении и мониторинге нескольких пациентов, страдающих миеломой. Цель этого обзора заключается в том, чтобы представить последние сведения о потенциале распространения миРНА в качестве прогнозирующих, диагностических и терапевтических биомаркеров в нескольких миеломах, устойчивых к бортезомибу. МЕТОДЫ: С эт