Polycomb-Mediated Disruption of an Androgen Receptor Feedback Loop Drives Castration-Resistant Prostate Cancer.
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. Cancer Res; 77(2); 412-22. ©2016 AACR.
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Ka-Wing
KW
Fong
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Jonathan C
JC
Zhao
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Jung
J
Kim
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Shangze
S
Li
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Yeqing A
YA
Yang
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Bing
B
Song
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan.
Laure
L
Rittie
Division of Biostatistics, Department of Population Health, New York University School of Medicine, New York, New York.
Ming
M
Hu
Department of Pathology, Northwestern University, Chicago, Illinois.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
Ximing
X
Yang
Sources et Méthodologie du Droit Economique, GREDEG-CREDECO CNRS UMR 7321 Université de Nice-Sophia Antipolis and International CCN Society, Nice, France.
Bernard
B
Perbal
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. jindan-yu@northwestern.edu.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
Jindan
J
Yu
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*
C410798:AR protein, human; C526319:CCN3 protein, human; D055514:Nephroblastoma Overexpressed Protein; D011944:Receptors, Androgen; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein