HBx-induced androgen receptor expression in HBV-associated hepatocarcinoma is independent of the methylation status of its promoter

Abstract

A remarkable feature of HBV-associated HCC is male predominance. The cooperation of hepatitis B virus X protein (HBx) with androgen receptor (AR) signaling pathway has been documented to contribute to this dominance. HBx, a multifunctional viral regulator, has been documented to induce promoter hypermethylation and low expression of tumor suppressor genes via activation of DNA methyltransferase (DNMT) in hepatocarcinogenesis. In prostate cancer, hypermethylation of AR promoter is associated with loss of AR expression. However, the relationship among HBx, DNMTs, the methylation status of AR and AR expression in HBV-associated HCC is still unknown. In this report, we found that HBx correlated with high levels of AR in HCC cases and induced AR expression by stimulating its transcription in liver cell lines. HBx correlated with high expression of DNMTs in HCC cases too. Both in vivo and in vitro, however, the expression of AR was not associated with its promoter methylation status, and the methylation status of AR was not regulated by DNMTs. AR expression is higher in peritumoral tissues than in tumors, as well as being higher in HBV-associated HCC than in HBV-negative cases. Therefore, HBx-induced high expression of AR plays a role during hepatocarcinogenesis, but is not involved with its promoter methylation or DNMTs. HBx-mediated DNMT deregulation is gene-specific, and the expression and methylated regulation of AR is tissue-specific.