title: ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
authors.forename: Junjian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
authors.forename: June X
authors.initials: JX
authors.lastname: Zou
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
authors.forename: Demin
authors.initials: D
authors.lastname: Cai
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Duan
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: Department of Urology, School of Medicine, University of California, Davis, Sacramento, California, USA.
authors.forename: Joy C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Louie
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: Department of Urology, School of Medicine, University of California, Davis, Sacramento, California, USA.|Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
authors.affiliation: Department of Urology, School of Medicine, University of California, Davis, Sacramento, California, USA.|Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Evans
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.|Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.affiliation: Shantou University Medical College, Shantou, China.
authors.forename: Jianzhen
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.|Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Gene Expression Laboratory, Salk Institute, Howard Hughes Medical Institute, Salk Institute, La Jolla, California, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.|Comprehensive Cancer Center, University of California, Davis, Sacramento, California, USA.|Veterans Affairs Northern California Health Care System-Mather, Mather, California, USA.
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002470:Cell Survival / Q000187:drug effects; D016208:Databases, Factual; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005956:Glucose-6-Phosphate Isomerase; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D020005:Propanols / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D014410:Tumor Stem Cell Assay
chemical_list: C575715:1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4'-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-(1,1'-biphenyl)-4-yl)propan-2-ol; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010879:Piperazines; D020005:Propanols; D012333:RNA, Messenger; C539900:RORC protein, human; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D005956:Glucose-6-Phosphate Isomerase