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EBioMedicine. 2018 Sep;35:155-166. doi: 10.1016/j.ebiom.2018.08.043. Epub 2018 Aug 24.

Androgen receptor drives hepatocellular carcinogenesis by activating enhancer of zeste homolog 2-mediated Wnt/β-catenin signaling.

Author information

1
Cancer Hospital, Harbin Medical University, Harbin, PR China.
2
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
3
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, PR China.
4
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China.
5
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China. Electronic address: alfredcheng@cuhk.edu.hk.
6
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, PR China. Electronic address: gaoyueqiu@hotmail.com.
7
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, PR China. Electronic address: fogsea@163.com.

Abstract

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; Epigenetics; Hepatocarcinogenesis; Wnt/β-catenin signaling

PMID:
30150059
PMCID:
PMC6156715
DOI:
10.1016/j.ebiom.2018.08.043
[Indexed for MEDLINE]
Free PMC Article

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