Polycomb-mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer

Ka Wing Fong, Jonathan C. Zhao, Jung Kim, Shangze Li, Yeqing A. Yang, Bing Song, Laure Rittie, Ming Hu, Ximing Yang, Bernard Perbal, Jindan Yu*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations


The lethal phenotype of castration-resistant prostate cancer (CRPC) is generally caused by augmented signaling from the androgen receptor (AR). Here, we report that the AR-repressed gene CCN3/NOV inhibits AR signaling and acts in a negative feedback loop to block AR function. Mechanistically, a cytoplasmic form of CCN3 interacted with the AR N-terminal domain to sequester AR in the cytoplasm of prostate cancer cells, thereby reducing AR transcriptional activity and inhibiting cell growth. However, constitutive repression of CCN3 by the Polycomb group protein EZH2 disrupted this negative feedback loop in both CRPC and enzalutamide-resistant prostate cancer cells. Notably, restoring CCN3 was sufficient to effectively reduce CPRC cell proliferation in vitro and to abolish xenograft tumor growth in vivo. Taken together, our findings establish CCN3 as a pivotal regulator of AR signaling and prostate cancer progression and suggest a functional intersection between Polycomb and AR signaling in CRPC.

Original languageEnglish (US)
Pages (from-to)412-422
Number of pages11
JournalCancer Research
Issue number2
StatePublished - Jan 15 2017


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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