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Activation of ONECUT2 by RB1 loss in castration-resistant prostate cancer

Chen Qian1, Qian Yang1, Stephen J Freedland1

  • 1Division of Cancer Biology and Therapeutics, Department of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA.

American Journal of Clinical and Experimental Urology
|January 13, 2023
PubMed

Insights

Loss of the RB1 tumor suppressor activates ONECUT2 (OC2) in castration-resistant prostate cancer (CRPC). This RB1 inactivation drives cancer progression and suggests RB1 activity as a biomarker for OC2-targeted therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Loss of TP53 and RB1 tumor suppressors is common in castration-resistant prostate cancer (CRPC).
  • These genetic alterations promote therapy resistance and lineage plasticity, contributing to CRPC progression.
  • ONECUT2 (OC2) is a transcription factor upregulated in CRPC, driving metastasis and neuroendocrine differentiation.

Purpose of the Study:

  • To investigate the role of RB1 loss in activating OC2 in metastatic CRPC (mCRPC).
  • To explore the mechanisms by which RB1 inactivation leads to OC2 upregulation.
  • To evaluate the therapeutic potential of targeting OC2 in RB1-deficient CRPC.

Main Methods:

  • Utilized human and mouse prostate cancer models with RB1 silencing.
  • Investigated epigenetic regulation of OC2.
  • Analyzed OC2 expression in human CRPC samples with varying RB1 status.
  • Tested a small molecule OC2 inhibitor in vitro and in vivo models.

Main Results:

  • RB1 silencing was sufficient to upregulate OC2 in prostate cancer models, partly via epigenetic mechanisms.
  • OC2 expression downregulated TP53 transcription and inactivated RB1 through phosphorylation.
  • OC2 activation in human CRPC correlated with RB1 loss and inversely with RB1 expression/activity.
  • OC2 inhibition blocked enzalutamide-induced lineage plasticity in vitro.

Conclusions:

  • RB1 inactivation is a key driver for OC2 activation in CRPC.
  • OC2 acts downstream of RB1 loss, promoting aggressive cancer phenotypes.
  • RB1 activity biomarkers may identify patients who would benefit from OC2-targeted therapies in hormone-refractory prostate cancer.
Keywords:
ONECUT2RB1TP53lineage plasticityprostate cancer

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