miRNA-548ah promotes the replication and expression of hepatitis B virus by targeting histone deacetylase 4

Abstract Aim Many studies have shown that some microRNAs (miRNAs) play an important role in the pathogenesis of chronic hepatitis B (CHB) infection. In this study, we aimed to explore the role and molecular mechanism of miRNA-548ah in the replication and expression of the hepatitis B virus (HBV). Main methods Overexpression and knockdown of miRNA-548ah were performed in three hepatoma cell lines with HBV replication and in a murine HBV model injected with adenovirus HBV vector. The effect of miRNA-548ah on its target gene, histone deacetylase (HDAC) 4, were confirmed in in vitro studies and further investigated in liver tissues from CHB patients. Key findings miRNA-548ah significantly increased the expression of HBV in hepatoma cell lines and in a HBV mouse model. The expression level of covalently closed circular DNA (cccDNA) in the miRNA-548ah mimics group was significantly higher than the negative control group and significantly lower in the miRNA-548ah inhibitor group. The HBV core antigen promotes the expression of miRNA-548ah in hepatocytes. Finally, we observed a negative correlation between the expression of miRNA-548ah and HDAC4 in the liver tissue of patients with CHB. Significance miRNA-548ah promoted the replication and expression of HBV through the regulation of the target gene, HDAC4. Inhibition of HDAC4 by miRNA-548ah might influence the deacetylation state of histones binding to cccDNA, thereby enhancing the replication of cccDNA. The HBV core antigen might increase the expression of miRNA-548ah. These results may provide new potential molecular targets for the prevention and treatment of CHB.