TY - JOUR
T1 - Polycomb-mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer
AU - Fong, Ka Wing
AU - Zhao, Jonathan C.
AU - Kim, Jung
AU - Li, Shangze
AU - Yang, Yeqing A.
AU - Song, Bing
AU - Rittie, Laure
AU - Hu, Ming
AU - Yang, Ximing
AU - Perbal, Bernard
AU - Yu, Jindan
N1 - Publisher Copyright:
©2016 AACR.
PY - 2017/1/15
Y1 - 2017/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85018162789&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018162789&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-1949
DO - 10.1158/0008-5472.CAN-16-1949
M3 - Article
C2 - 27815387
AN - SCOPUS:85018162789
SN - 0008-5472
VL - 77
SP - 412
EP - 422
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -