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

doi:10.1158/0008-5472.CAN-16-1949

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

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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 language	English
Pages (from-to)	412-422
Number of pages	11
Journal	Cancer Research
Volume	77
Issue number	2
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-1949
State	Published - Jan 15 2017

Bibliographical note

Funding Information:
We thank members of the Yu laboratory for helpful discussions. Tissue microarrays were provided by the Northwestern University prostate cancer SPORE (P50 CA180995). Cell Biology studies were performed in the Center for Advanced Microscopy/Nikon Imaging Center (CAM). This work was supported in part by the Research Scholar AwardRSG-12-085-01 (J. Yu) from the American Cancer Society and R01CA172384 (J. Yu) and P50 CA180995 (J. Yu) from the NIH. Y.A. Yang was supported in part by the NIH/NCI training grant T32 CA09560 and J. Kim was supported in part by the Institutional Ruth L. Kirschstein National Research Service Award from the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007169). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
©2016 AACR.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Polycomb-mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer",

abstract = "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.",

author = "Fong, {Ka Wing} and Zhao, {Jonathan C.} and Jung Kim and Shangze Li and Yang, {Yeqing A.} and Bing Song and Laure Rittie and Ming Hu and Ximing Yang and Bernard Perbal and Jindan Yu",

note = "Funding Information: We thank members of the Yu laboratory for helpful discussions. Tissue microarrays were provided by the Northwestern University prostate cancer SPORE (P50 CA180995). Cell Biology studies were performed in the Center for Advanced Microscopy/Nikon Imaging Center (CAM). This work was supported in part by the Research Scholar AwardRSG-12-085-01 (J. Yu) from the American Cancer Society and R01CA172384 (J. Yu) and P50 CA180995 (J. Yu) from the NIH. Y.A. Yang was supported in part by the NIH/NCI training grant T32 CA09560 and J. Kim was supported in part by the Institutional Ruth L. Kirschstein National Research Service Award from the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007169). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2016 AACR.",

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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