ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- Targeting the Epigenome in Colorectal Cancer.International journal of molecular sciences · 2026Review
- Piperine as a Multifunctional Epigenetic Modulator: Integrative Molecular Insights into Cancer and Chronic Disease Therapy.International journal of molecular sciences · 2026Review
- Mechanisms biomarkers and therapeutic strategies of human endogenous retroviruses in cancer.Discover oncology · 2026Review
- Epigenetic regulation in cancer metastasis.Discover oncology · 2026Review
- Chromatin Accessibility in Cancer: Biological Functions, Mechanisms, Therapeutic Potential, and Future Directions.MedComm · 2026Review
- Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.Nature communications · 2026Article
- Cancer stem cell-driven drug resistance in colorectal carcinoma: molecular aspects and therapeutic potentials.Molecular cancer · 2026Review
- The Great Potential of DNA Methylation in Triple-Negative Breast Cancer: From Biological Basics to Clinical Application.Biomedicines · 2026Review
- Gut microbiota drives cancer evolution and therapy resistance.Molecular cancer · 2026Review
- Deciphering pathogenic mechanisms of BDCPP exposure in endometrial cancer progression via an integrated approach combining network toxicology, machine learning, and molecular docking.International journal of surgery (London, England) · 2026Article
- The resilient subset: cancer stem cells at the core of immunotherapy resistance.Immunotherapy advances · 2026Review
- Functional modules predict cancer-relevant genetic interactions in mammalian cells.bioRxiv : the preprint server for biology · 2025Article
- DNA, RNA, and histone methylation regulation enzymes and their crosstalk in colorectal carcinogenesis and progression: a review of molecular mechanisms, clinical implications, and future perspectives.Cellular & molecular biology letters · 2025Review
- Targeting epigenetic regulators as a promising avenue to overcome cancer therapy resistance.Signal transduction and targeted therapy · 2025Review
- Decoding colorectal cancer targeted therapy: a bibliometric journey of the last decade (2015-2024).Discover oncology · 2025Article
- A pan-cancer analysis reveals the oncogenic and immunological role of insulin-like growth factor 2 mRNA-binding protein family members.Discover oncology · 2025Article
- UnravelingCancer drug resistance (Alhambra, Calif.) · 2025Article
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Authors and funding
16 authors.
Funding
Abstract
purposeBRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo. EXPERIMENTAL
designWe randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.
resultsA profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions, suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor-suppressor genes. Combined inhibition of PRC activity through EZH2 inhibition with 5-azacitidine treatment additively improved efficacies in BRAFV600E colorectal cancer cells.
conclusionsIn conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E colorectal cancer, and simultaneous blockade of DNA methyltransferase and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated colorectal cancer.
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