ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Junjian Wang; June X Zou; Xiaoqian Xue; Demin Cai; Yan Zhang; Zhijian Duan; Qiuping Xiang; Joy C Yang; Maggie C Louie; Alexander D Borowsky; Allen C Gao; Christopher P Evans; Kit S Lam; Jianzhen Xu; Hsing-Jien Kung; Ronald M Evans; Yong Xu; Hong-Wu Chen

doi:10.1038/nm.4070

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Nat Med. 2016 May;22(5):488-96. doi: 10.1038/nm.4070. Epub 2016 Mar 28.

Authors

Junjian Wang¹, June X Zou¹, Xiaoqian Xue², Demin Cai¹, Yan Zhang², Zhijian Duan¹, Qiuping Xiang², Joy C Yang³, Maggie C Louie⁴, Alexander D Borowsky⁵, Allen C Gao^{3

6}, Christopher P Evans^{3

6}, Kit S Lam^{1

6}, Jianzhen Xu⁷, Hsing-Jien Kung^{1

6}, Ronald M Evans⁸, Yong Xu², Hong-Wu Chen^{1

6

9}

Affiliations

¹ Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
² Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
³ Department of Urology, School of Medicine, University of California, Davis, Sacramento, California, USA.
⁴ Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA.
⁵ Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
⁶ Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.
⁷ Shantou University Medical College, Shantou, China.
⁸ Gene Expression Laboratory, Salk Institute, Howard Hughes Medical Institute, Salk Institute, La Jolla, California, USA.
⁹ Veterans Affairs Northern California Health Care System-Mather, Mather, California, USA.

PMID: 27019329
PMCID: PMC5030109
DOI: 10.1038/nm.4070

Abstract

The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzamides
Cell Survival / drug effects
Databases, Factual
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
Glucose-6-Phosphate Isomerase
Humans
Immunoblotting
Immunohistochemistry
Male
Mice
Neoplasm Transplantation
Nitriles
Nuclear Receptor Coactivator 1 / metabolism
Nuclear Receptor Coactivator 3 / metabolism
Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
Phenylthiohydantoin / analogs & derivatives
Phenylthiohydantoin / pharmacology
Piperazines / pharmacology
Propanols / pharmacology
Prostatic Neoplasms, Castration-Resistant / genetics*
Prostatic Neoplasms, Castration-Resistant / metabolism
RNA, Messenger / metabolism
Real-Time Polymerase Chain Reaction
Receptors, Androgen / genetics*
Receptors, Androgen / metabolism
Response Elements
Tumor Stem Cell Assay

Substances

1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4'-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-(1,1'-biphenyl)-4-yl)propan-2-ol
Antineoplastic Agents
Benzamides
Nitriles
Nuclear Receptor Subfamily 1, Group F, Member 3
Piperazines
Propanols
RNA, Messenger
RORC protein, human
Receptors, Androgen
Phenylthiohydantoin
enzalutamide
NCOA1 protein, human
NCOA3 protein, human
Nuclear Receptor Coactivator 1
Nuclear Receptor Coactivator 3
Glucose-6-Phosphate Isomerase

Abstract

MeSH terms

Substances

Grants and funding