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

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

Author information

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.

PMID:
30478421
PMCID:
PMC6614557
DOI:
10.1038/s41591-018-0241-1
[Indexed for MEDLINE]
Free PMC Article

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