Androgen receptor drives hepatocellular carcinogenesis by activating enhancer of zeste homolog 2-mediated Wnt/β-catenin signalingResearch in context
Haibin Song,
Zhuo Yu,
Xuehua Sun,
Jun Feng,
Qi Yu,
Hanif Khan,
Xiaojun Zhu,
Lingying Huang,
Man Li,
Myth T.S. Mok,
Alfred S.L. Cheng,
Yueqiu Gao,
Hai Feng
Affiliations
Haibin Song
Cancer Hospital, Harbin Medical University, Harbin, PR China
Zhuo Yu
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
Xuehua Sun
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
Jun Feng
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, PR China
Qi Yu
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, PR China
Hanif Khan
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, PR China
Xiaojun Zhu
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
Lingying Huang
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
Man Li
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
Myth T.S. Mok
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China
Alfred S.L. Cheng
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China; Correspondence to: A. S. L. Cheng School of Biomedical Sciences, Room 405, Lo Kwee-Seong Integrated Biomedical Sciences Building in Area 39, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Yueqiu Gao
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China; Correspondence to: Y. Gao Liver Disease Department, No.528. Zhangheng Road, Pudong New District, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Hai Feng
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, PR China; Correspondence to: H. Feng No.157, Baojian Road, Nangang District, Harbin Medical University, Harbin, Heilongjiang Province, China.
Background: Androgen receptor (AR) plays a crucial role as a transcription factor in promoting the development of hepatocellular carcinoma (HCC) which is prone to aberrant chromatin modifications. However, the regulatory effects of AR on epigenetic mediators in HCC remain ill-defined. Enhancer of zeste homolog 2 (EZH2), an oncogene responsible for the tri-methylation of histone H3 at lysine 27 (H3K27me3), was identified to be overexpressed in approximate 70–90% of HCC cases, which prompted us to investigate whether or how AR regulates EZH2 expression. Methods: Colony formation, soft agar assay, xenograft and orthotopic mouse models were used to determine cell proliferation and tumorigenicity of gene-manipulated HCC cells. Gene regulation was assessed by chromatin immunoprecipitation, luciferase reporter assay, quantitative RT-PCR and immunoblotting. Clinical relevance of candidate proteins in patient specimens was examined in terms of pathological parameters and postsurgical survival rates. Findings: In this study, we found that AR upregulated EZH2 expression by binding to EZH2 promoter and stimulating its transcriptional activity. EZH2 overexpression increased H3K27me3 levels and thereby silenced the expression of Wnt signal inhibitors, resulting in activation of Wnt/β-catenin signaling and subsequently induction of cell proliferation and tumorigenesis. In a cohort of human HCC patients, concordant overexpression of AR, EZH2, H3K27me3 and active β-catenin was observed in tumor tissues compared with paired non-tumor tissues, which correlated with tumor progression and poor prognosis. These findings demonstrate a novel working model in which EZH2 mediates AR-induced Wnt/β-catenin signaling activation through epigenetic modification, and support the application of EZH2-targeted reagents for treating HCC patients. Keywords: Androgen receptor, EZH2, Wnt/β-catenin signaling, Hepatocarcinogenesis, Epigenetics
