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Updated: Feb 2, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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

Mirja Rotinen1, Sungyong You1, Julie Yang1

  • 1Division of Cancer Biology and Therapeutics, Departments of Surgery & Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Nature Medicine
|November 28, 2018
PubMed

Insights

ONECUT2 (OC2) drives aggressive prostate cancer by overriding androgen receptor (AR) pathways in metastatic castration-resistant prostate cancer (mCRPC). Inhibiting OC2 with a new drug suppressed metastasis in mice, offering a potential new treatment target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Androgen suppression therapy for prostate cancer (PC) can lead to aggressive, androgen receptor (AR)-independent variants.
  • Metastatic castration-resistant prostate cancer (mCRPC) represents an advanced stage with limited treatment options.

Purpose of the Study:

  • To identify key regulators of AR-independent aggressive prostate cancer.
  • To investigate the role of transcription factor ONECUT2 (OC2) in mCRPC.
  • To evaluate OC2 as a potential therapeutic target.

Main Methods:

  • Investigated the function of ONECUT2 (OC2) in mCRPC models.
  • Analyzed OC2's regulation of AR target genes and FOXA1.
  • Assessed OC2 activity in human prostate cancer tissues.
  • Tested a novel small molecule inhibitor of OC2 in mouse models of metastasis.

Main Results:

  • ONECUT2 (OC2) was identified as a master regulator of AR networks in mCRPC.
  • OC2 functions as a survival factor, suppresses AR signaling, and promotes neural differentiation and lethal disease progression.
  • OC2 is active in a significant portion of human prostate adenocarcinomas and neuroendocrine tumors.
  • Inhibition of OC2 suppressed metastasis in preclinical mouse models.

Conclusions:

  • OC2 can displace AR-dependent growth and survival mechanisms in mCRPC, even when AR is expressed but bypassed.
  • OC2 represents a promising drug target for aggressive, metastatic prostate cancer.

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