INTERNATIONAL CONGRESS OF
CancerGenetics
Epigenetic Therapies Against Virus-Driven Cancers: A New Frontier
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Faezeh Arghidash,1,*
1. Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Introduction: Oncogenic viruses contribute to human cancer not only by integrating into host genomes or expressing viral oncoproteins, but also by reconfiguring the host cell epigenetic landscape. Through alterations in DNA methylation, histone modifications, and chromatin organization, these viruses reshape transcriptional programs that govern cell proliferation, differentiation, and immune evasion. Emerging evidence suggests that virus-driven epigenetic remodeling imprints lasting “epigenetic scars” that sustain malignant phenotypes even after initial viral triggers subside. Understanding these epigenetic mechanisms is critical for identifying biomarkers of virus associated cancers and for developing therapies that target epigenetic regulators in conjunction with antiviral and immunotherapeutic strategies (1-3). Mechanistically, viral oncoproteins and viral RNAs interact with DNA methyltransferases, histone-modifying enzymes, and chromatin remodelers to establish promoter hypermethylation, silencing tumor suppressors, and mobilizing enhancers that drive oncogenic transcriptional networks (4). The resulting chromatin remodeling can alter 3D genome architecture, including topologically associating domains and enhancer-promoter contacts, thereby linking viral infection to widespread shifts in gene expression. These changes often accompany immune escape, stemness features, and epithelial-mesenchymal transition, contributing to tumor initiation, progression, and therapy resistance (1-3). Therapeutically, epigenetic drugs such as DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and Enhancer of zeste homolog 2 (EZH2) inhibitors, alone or in combination with antiviral or immune based therapies, show promise in preclinical models of virus-associated cancers (4). A deeper integration of virology, epigenetics, and oncology is needed to translate these findings into precise, patient-tailored interventions and to identify predictive biomarkers, including methylation signatures and chromatin-state profiles, that guide treatment selection.
- Methods: The present study was conducted based on the review of published studies in PubMed, Scopus, and Web of Science, and all studies were reviewed until 2025.
- Results: The study demonstrates that oncogenic viruses drive widespread epigenetic remodeling across multiple cancer types, evidenced by consistent shifts in DNA methylation, histone modification patterns, and chromatin accessibility at key regulatory regions. Viral oncoproteins and associated noncoding RNAs interact with host epigenetic modifiers such as DNA methyltransferases, histone deacetylases, histone acetyltransferases, and polycomb repressive complex 2 (PRC2) components, correlating with promoter hypermethylation and repression of tumor suppressor genes while simultaneously activating oncogenic enhancer landscapes. These epigenomic changes are accompanied by alterations in 3D genome organization, including disruptions to topologically associating domains and promoter enhancer contacts, which align with coordinated transcriptional reprogramming of pathways governing cell cycle progression, apoptosis avoidance, immune evasion, and stemness. The epigenetic landscape exhibits virus-type specific signatures, with HPV-associated cancers showing distinct methylation and chromatin marks compared with EBV- or HBV/HCV-associated malignancies, yet all share common themes of promoter silencing and enhancer reactivation. Therapeutically, combining epigenetic drugs such as DNMT inhibitors, HDAC inhibitors, and EZH2 inhibitors with antiviral or immunotherapeutic strategies yields additive or synergistic effects in preclinical models, including reactivation of silenced tumor suppressors and enhanced tumor cell immunogenicity. Biomarker analyses reveal methylation patterns and chromatin-state profiles capable of distinguishing virus-driven tumors from non-virus-associated cancers, holding promise for patient stratification and monitoring responses to epigenetic therapies.
- Conclusion: Oncogenic viruses rewire the host epigenome in cancer, creating durable changes in DNA methylation, histone landscapes, and chromatin structure that sustain malignant phenotypes beyond the initial infection. These epigenetic alterations drive rewired transcriptional programs supporting proliferation, apoptosis resistance, immune evasion, and stem-like features, fueling tumor initiation and progression. While there is virus type specific signatures, common themes such as promoter silencing of tumor suppressors and enhancer reactivation emerge across virus- associated cancers. Integrating epigenetic therapies with antiviral and immunotherapies shows promise to restore tumor suppressor function and modulate the immune microenvironment, potentially improving outcomes. Future work should focus on precise, patient-tailored interventions and robust epigenetic biomarkers to predict response to combined regimens.
- Keywords: Oncogenic virus, Epigenome, Cancer, Immune modulation.
