Signal activation of hepatitis B virus-related hepatocarcinogenesis by upregulation of SUV39h1.

BACKGROUND HBx associates with hepatocellular carcinogenesis via the induction of malignant transformation and mitochondrial dysfunction. However, the association between HBx and histone methyltransferase in carcinogenesis has not been fully clarified. In this study, we analyzed the association between HBx and the histone methyltransferase SUV39h1 using HBV replication models. METHODS We constructed several HBx and SUV39h1 expression plasmids and analyzed the association between HBx and SUV39h1 with respect to hepatitis B virus (HBV) replication and hepatocarcinogenesis. RESULTS SUV39h1 upregulation was observed in HBV-infected humanized mouse livers and clinical HBV-related hepatocellular carcinoma tissues, indicating that SUV39h1 expression might be regulated by HBV infection. Through in vitro analysis, we determined that the co-activator domain of HBx interacts with the PSET and SET domains of SUV39h1. The expression levels of four genes, ATF6, AFP, GADD45a, and DUSP1, known to induce carcinogenesis via HBx expression, were upregulated by HBx and further upregulated in the presence of both HBx and SUV39h1. Furthermore, histone methyltransferase activity, the main function of SUV39h1, was enhanced in the presence of HBx. CONCLUSIONS We demonstrated that SUV39h1 and HBx enhance each other's activity, leading to HBx-mediated hepatocarcinogenesis. We propose that regulation of this interaction could help to suppress development of hepatocellular carcinoma.