Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level.
Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBV-related HCC is the male predominance, with a male to female ratio of 5-7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.
Chiu
Chi-Ming
CM
Department of Microbiology, Graduate Institute of Clinical Medicine, Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Yeh
Shiou-Hwei
SH
Chen
Pei-Jer
PJ
Kuo
Ti-Jung
TJ
Chang
Ching-Ju
CJ
Chen
Po-Jen
PJ
Yang
Wan-Jen
WJ
Chen
Ding-Shinn
DS
D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006509:Hepatitis B; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013234:Stem Cells; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D000728:Androgens; D011944:Receptors, Androgen; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D016392:Proto-Oncogene Proteins pp60(c-src)