ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Mirja Rotinen; Sungyong You; Julie Yang; Simon G Coetzee; Mariana Reis-Sobreiro; Wen-Chin Huang; Fangjin Huang; Xinlei Pan; Alberto Yáñez; Dennis J Hazelett; Chia-Yi Chu; Kenneth Steadman; Colm M Morrissey; Peter S Nelson; Eva Corey; Leland W K Chung; Stephen J Freedland; Dolores Di Vizio; Isla P Garraway; Ramachandran Murali; Beatrice S Knudsen; Michael R Freeman

doi:10.1038/s41591-018-0241-1

ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Nat Med. 2018 Dec;24(12):1887-1898. doi: 10.1038/s41591-018-0241-1. Epub 2018 Nov 26.

Authors

Mirja Rotinen¹, Sungyong You¹, Julie Yang¹, Simon G Coetzee², Mariana Reis-Sobreiro¹, Wen-Chin Huang^{1

3}, Fangjin Huang¹, Xinlei Pan⁴, Alberto Yáñez⁵, Dennis J Hazelett², Chia-Yi Chu⁶, Kenneth Steadman¹, Colm M Morrissey⁷, Peter S Nelson⁸, Eva Corey⁷, Leland W K Chung⁶, Stephen J Freedland¹, Dolores Di Vizio¹, Isla P Garraway⁹, Ramachandran Murali⁴, Beatrice S Knudsen¹, Michael R Freeman¹⁰

Affiliations

¹ Division of Cancer Biology and Therapeutics, Departments of Surgery & Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² The Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
⁴ Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Department of Urology, University of Washington, Seattle, WA, USA.
⁸ Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹ Department of Urology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ Division of Cancer Biology and Therapeutics, Departments of Surgery & Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. michael.freeman@cshs.org.

Abstract

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenocarcinoma / drug therapy*
Adenocarcinoma / genetics
Adenocarcinoma / pathology
Androgens / genetics
Androgens / metabolism
Animals
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic / drug effects
Hepatocyte Nuclear Factor 3-alpha / genetics*
Homeodomain Proteins / antagonists & inhibitors
Homeodomain Proteins / genetics*
Humans
Male
Mice
Neuroendocrine Tumors / genetics
Neuroendocrine Tumors / pathology
Prostatic Neoplasms, Castration-Resistant / drug therapy*
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / pathology
Receptors, Androgen / genetics*
Signal Transduction
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics*
Xenograft Model Antitumor Assays

Substances

AR protein, human
Androgens
FOXA1 protein, human
Hepatocyte Nuclear Factor 3-alpha
Homeodomain Proteins
ONECUT2 protein, human
Receptors, Androgen
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding