Figure 1.

HCV induces epigenetic alterations that persist following cure with DAAs and may be reverted by drugs. HCV infection directly, or via induction of inflammation, stimulates cellular pathways that lead to the activation of epigenetic modifying enzymes and nuclear complexes, such as DNMTs, HATs, HDACs, BRD4 and MLL/WDR5 complexes, which execute genome-wide repositioning of PTMs and DNA methylation, and the reprograming of host gene expression. Consequently, pathways related to cancer are activated, contributing to HCC development and progression. The epigenetic changes remain persistent following cure of infection by DAAs therapy, thus maintaining the risk for HCC development. Drugs that prevent the induction of upstream pathways leading to activation of epigenetic modifiers or drugs that inhibit the function of the epigenetic modifiers downstream, may revert the epigenetic signature and prevent HCC development. DNMTs, DNA methyltransferases; HAT, histone acetyl transferase; HDAC, histone deacetylase; BRD4, Bromodomain-containing protein 4; PTEF-b, the positive transcription elongation factor; RNAP II, RNA polymerase II; URS, upstream repressive sequence; MLL, mixed-lineage leukemia protein; WDR5, WD Repeat Domain 5; RbBP5, RB Binding Protein 5; Ash2L, ASH2 Like.