Hepatitis B Virus X Protein Enhances the Transcriptional Activity of the Androgen Receptor Through c-Src and Glycogen Synthase Kinase-3β Kinase Pathways

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurs predominantly in men. By enhancing the transcriptional activity of the androgen receptor (AR) gene in a ligand-dependent manner, the HBV X protein (HBx) might contribute to this disparity between sexes. To dissect the mechanisms underlying HBx-enhanced AR transactivation, we investigated the effect of HBx on two critical steps in the regulation of ligand-stimulated AR activities. One step is the dimerization of AR (through the interaction of its N-termini and C-termini), and the other step is the activation of the AR N-terminal transactivation domain (NTD). HBx increased the NTD activation of the AR through c-Src kinase. HBx also enhanced AR dimerization by inhibiting glycogen synthase kinase-3 beta (GSK-3 beta) activity, which acts as a negative regulator of the interaction between AR and the N-termini and C-termini. The HBx-enhanced AR transactivation was abolished by blocking c-Src and activating GSK-3 beta kinases simultaneously, suggesting that these two kinases act as major switches in the activation process. The regulatory function of both kinases has been further verified in primary hepatocytes isolated from the livers of HBx transgenic male mice. Conclusion: Our study thus identified two key kinases through which HBx enhances the AR transcriptional activity. These kinases might be potential candidates for future prevention or therapy for HBV-related HCC in men. (HEPATOLOGY 2009;49:1515-1524.)