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Updated: Mar 12, 2026

Murine Prostate Micro-dissection and Surgical Castration
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Murine Prostate Micro-dissection and Surgical Castration

Published on: May 11, 2016

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Polycomb-Mediated Disruption of an Androgen Receptor Feedback Loop Drives Castration-Resistant Prostate Cancer

Ka-Wing Fong1, Jonathan C Zhao1, Jung Kim1

  • 1Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Cancer Research
|November 6, 2016
PubMed

Insights

The androgen receptor (AR) drives prostate cancer. The AR-repressed gene CCN3 inhibits AR signaling by sequestering AR in the cytoplasm, blocking cancer growth. Restoring CCN3 reduces castration-resistant prostate cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Castration-resistant prostate cancer (CRPC) is driven by amplified androgen receptor (AR) signaling.
  • The AR-repressed gene CCN3/NOV is investigated for its role in regulating AR signaling.
  • Understanding negative feedback loops in CRPC is crucial for developing new therapies.

Purpose of the Study:

  • To investigate the role of CCN3 in regulating AR signaling in prostate cancer.
  • To elucidate the mechanism by which CCN3 inhibits AR function.
  • To determine if CCN3 can be therapeutically targeted to treat CRPC.

Main Methods:

  • Western blotting and immunoprecipitation to detect CCN3 and AR interactions.
  • Cell proliferation assays to assess the impact of CCN3 on prostate cancer cell growth.
  • Xenograft models in mice to evaluate the in vivo efficacy of CCN3 restoration.

Main Results:

  • CCN3 directly interacts with the N-terminal domain of AR, sequestering it in the cytoplasm.
  • This cytoplasmic sequestration reduces AR transcriptional activity and inhibits prostate cancer cell proliferation.
  • Constitutive repression of CCN3 by EZH2 disrupts this feedback loop in CRPC and enzalutamide-resistant cells.
  • Restoring CCN3 expression significantly reduces CRPC cell proliferation in vitro and tumor growth in vivo.

Conclusions:

  • CCN3 acts as a negative regulator of AR signaling through cytoplasmic sequestration.
  • Disruption of the CCN3-AR feedback loop by EZH2 contributes to CRPC progression.
  • Restoring CCN3 is a potential therapeutic strategy for castration-resistant prostate cancer.

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