Epigenetic Regulation of MicroRNA Expression by Hepatitis B Virus Pre‐S2 Mutant Promotes Hepatocellular Carcinoma Tumorigenesis

BACKGROUND & AIMS: Discovery of therapeutic targets for hepatocellular carcinoma (HCC) is urgently needed. As an important hepatitis B virus (HBV) oncoprotein, pre-S2 mutant activates multiple signalling pathways to induce HCC development. METHODS: This study investigated the effect of pre-S2 mutant on regulating microRNA (miRNA) expression and the role of miRNAs in mediating pre-S2 mutant's oncogenic functions. RESULTS: The results showed that 9 miRNAs were downregulated in both tumour tissues of pre-S2 mutant-positive HCC patients and pre-S2 mutant-expressed human HCC cell lines, contributing to pre-S2 mutant-promoted cell proliferation, anchorage-independent cell growth, cell cycle progression, and tumour growth and malignancy. Moreover, pre-S2 mutant downregulated miRNA expression at the epigenetic levels through suppression of lysine acetyltransferase 3B (KAT3B)- and KAT5-mediated histone H3 lysine 9 acetylation (H3K9ac) and H4K5ac modifications. The decreased levels of pre-S2 mutant-dysregulated miRNAs could also be detected in blood exosomes of patients. CONCLUSIONS: Collectively, this study provided new mechanistic insights and therapeutic perspectives for pre-S2 mutant-associated HCC tumorigenesis.