Lisette Pham

Background: Hepatitis C virus (HCV) is a global health burden, chronically infecting approximately 58 million individuals worldwide and remaining a leading infectious cause of hepatocellular carcinoma (HCC). The advent of direct-acting antivirals (DAAs) has transformed HCV treatment, achieving sustained virologic response (SVR) rates exceeding 95%. However, epidemiologic data reveal a persistent HCC incidence of 1–2% per year following viral eradication, even among patients without advanced fibrosis. Known clinical risk factors such as cirrhosis stage, age, and metabolic syndrome fail to fully account for this residual cancer risk, suggesting a molecular alteration established during chronic infection that outlasts the virus itself. One candidate mechanism is epigenetic reprogramming: HCV infection has been shown to induce widespread histone H3 lysine 27 acetylation (H3K27ac) at enhancer regions in hepatocytes, increasing chromatin accessibility and oncogene expression. Whether these epigenetic marks persist after viral cure, and whether they drive continued oncogenic transcription through chromatin readers such as BRD4, has been the subject of emerging mechanistic investigation.

Objective: This narrative review examines the mechanistic evidence that HCV-induced epigenetic reprogramming persists after viral eradication and promotes hepatocarcinogenesis through BRD4-mediated transcriptional activation of oncogenic enhancer programs.

Search Methods: A literature search was conducted using the PubMed database for articles published between 2017 and 2023. Search terms included: “epigenetics hepatocellular carcinoma,” “HCV epigenome,” “H3K27ac liver,” “enhancer remodeling hepatitis C,” “BET bromodomain inhibitor liver cancer,” “BRD4 HCC,” and “sustained virologic response HCC risk.”

Results: ChIP-seq for H3K27ac performed on liver biopsies from chronic HCV patients, post-SVR patients, and uninfected controls identified approximately 5,300 differential H3K27ac peaks between HCV-infected and control tissue.^¹ Approximately 1,500 of these enhancer regions were found to remain persistently acetylated after viral clearance, with associated dysregulation of over 1,000 genes involved in cell cycle progression, MYC signaling, and inflammatory pathways.^¹ These findings were corroborated by genome-wide epigenomic profiling, which demonstrated that more than 40% of HCV-induced chromatin accessibility changes persisted following DAA-mediated cure and that approximately 1,200 genes remained transcriptionally dysregulated, including those governing Wnt signaling and cell proliferation.^² The functional significance of this epigenetic memory was established through pharmacologic BET bromodomain inhibition with JQ1, which reduced transcription of enhancer-associated oncogenes by 30–50% and suppressed over 60% of proliferative transcriptional programs in experimental liver disease models, with significant reductions in tumor burden in vivo.^³ It was further shown that BRD4, a BET family member, is enriched at super-enhancers controlling MYC, E2F targets, and cell cycle regulators in HCC cell lines; selective inhibition with AZD5153 downregulated over 700 tumor-promoting genes and reduced HCC cell proliferation by 50–70%.^⁴

Conclusion: Collectively, these studies support a mechanistic model in which HCV infection establishes a stable H3K27ac enhancer landscape that persists after viral eradication, is functionally maintained by BET chromatin readers, and sustains oncogenic transcription through BRD4-mediated super-enhancer activity. This epigenetic memory provides a plausible molecular basis for the residual HCC risk observed in post-SVR patients and identifies BRD4 as a potential therapeutic target for chemoprevention. Future investigations should validate BRD4 occupancy at HCV-induced enhancers in human post-SVR liver biopsies, develop H3K27ac-based biomarkers for HCC risk stratification, and explore liver-targeted delivery strategies for BET inhibitors to minimize systemic toxicity.

Works Cited:

1. Hamdane N, Jühling F, Crouchet E, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology. 2019;156(8):2313-2329.e7.
2. Perez S, Kaspi A, Domovitz T, et al. Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet. 2019;15(6):e1008181.
3. Jühling F, Hamdane N, Crouchet E, et al. Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut. 2021;70(1):157-169.
4. Lin Y, Wu T, Yao Q, et al. BRD4 promotes the progression of hepatocellular carcinoma through regulation of its target genes MYC and CCND1. Oncol Rep. 2020;43(2):580-588.
5. Kanwal F, Kramer J, Asch SM, et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology. 2017;153(4):996-1005.e1.