INTERNATIONAL CONGRESS OF
CancerGenetics
Epigenetic Regulation and Therapeutic Implications in Hereditary Cancers
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zahra sohrabi nasr ,1,*
1. yazd university
- Introduction: Epigenetic regulation refers to heritable and reversible changes in gene expression that occur without alterations in the DNA sequence. The major mechanisms include DNA methylation, histone modifications, and chromatin remodeling, all of which profoundly affect cellular identity, differentiation, and disease development. In hereditary cancers, germline mutations in epigenetic regulators predispose individuals to tumorigenesis, while subsequent somatic mutations amplify deregulated transcriptional programs. For example, alterations in chromatin regulators such as CREBBP, EP300, and NSD1 disrupt normal histone acetylation or methylation, predisposing cells to malignant transformation. These disruptions are further reinforced by aberrant DNA methylation patterns and deregulated histone modification landscapes that silence tumor suppressors or activate oncogenes. Thus, understanding epigenetic dysregulation in hereditary cancers is central to both mechanistic insight and therapeutic innovation.
- Methods: This review synthesizes findings from a wide range of experimental and clinical studies on the role of epigenetics in hereditary cancers. Literature was drawn from peer-reviewed sources focusing on the molecular basis of DNA methylation, histone modifications, and microRNA regulation, alongside therapeutic strategies targeting these processes. Clinical trials of epigenetic inhibitors such as DNMT inhibitors, HDAC inhibitors, and EZH2 inhibitors were prioritized, together with preclinical studies exploring novel drug combinations. Studies addressing resistance mechanisms, biomarker development, and next-generation therapeutic approaches were included to provide a comprehensive overview. Information was critically integrated to highlight both established knowledge and emerging directions in epigenetic therapy.
- Results: Epigenetic abnormalities are pervasive in hereditary cancers. DNA methylation, mediated by DNA methyltransferases, ensures stability of gene expression across cell divisions. However, hypermethylation of CpG islands in promoter regions frequently silences tumor suppressor genes, while global hypomethylation destabilizes the genome. Proteins such as MeCP2 and MBD2 reinforce repression by binding methylated DNA. Histone modifications, which encode a complex “histone code,” include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Loss of critical marks, such as H4K16 acetylation and H4K20 trimethylation, is consistently associated with malignancy and genomic instability. Dysregulated histone methyltransferases, such as EZH2, and demethylases like LSD1 and JMJD2C, act as oncogenic drivers by reprogramming chromatin and suppressing tumor suppressor transcription. MicroRNAs add an additional layer of regulation, with oncogenic miRNAs such as miR-21 or miR-155 promoting malignancy, while tumor suppressive miRNAs like miR-15/16 are often lost. These mechanisms collectively generate transcriptional reprogramming that fuels tumor heterogeneity and therapy resistance. From a therapeutic perspective, targeting epigenetic regulators has shown significant promise. DNMT inhibitors such as 5-azacitidine and decitabine re-activate silenced tumor suppressors by reversing aberrant methylation. HDAC inhibitors like vorinostat restore histone acetylation balance, leading to cell cycle arrest, apoptosis, or differentiation. Although these agents have shown success in hematological malignancies, their activity in solid tumors remains limited due to pharmacologic resistance and tumor heterogeneity. Combination therapies provide a solution: DNMT inhibitors enhance the efficacy of immune checkpoint inhibitors by inducing interferon signaling and increasing tumor immunogenicity, while HDAC inhibitors sensitize resistant cells to chemotherapy and radiotherapy. Next-generation inhibitors broaden therapeutic opportunities. EZH2 inhibitors such as tazemetostat show activity in lymphomas and sarcomas, while BET inhibitors targeting BRD4 suppress transcriptional programs driven by oncogenes like MYC. Together, these approaches highlight the therapeutic potential of epigenetic modulation in hereditary cancers.
- Conclusion: The accumulated evidence demonstrates that epigenetic dysregulation is not merely a secondary feature but a central driver of hereditary cancer development. Importantly, unlike genetic mutations, epigenetic alterations are reversible, making them attractive therapeutic targets. Nevertheless, clinical challenges remain: resistance to epigenetic drugs can arise from altered drug metabolism, mutations in epigenetic enzymes, or compensatory oncogenic signaling. Predictive biomarkers are urgently needed to stratify patients and optimize therapy. Functional epigenomics and multi-omics profiling promise to identify such markers, guiding precision approaches tailored to each tumor’s genetic and epigenetic context. Combination strategies are particularly promising, whether pairing epigenetic drugs with kinase inhibitors, hormone therapies, or immune checkpoint blockade. Advances in drug delivery, including nanoparticle-based systems, may further enhance efficacy and reduce off-target toxicity. Ultimately, co-targeting oncogenic signaling and epigenetic regulation provides a powerful paradigm to reprogram malignant cells, restore normal gene expression, and improve outcomes in hereditary cancers.
- Keywords: Epigenetics Hereditary cancers DNA methylation Histone modifications Epigenetic therapy
