EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent

Kexin Xu(Harvard University), Zhenhua J. Wu(Dana-Farber Cancer Institute), Anna C. Groner(Harvard University), Housheng Hansen He(Harvard University), Changmeng Cai(Beth Israel Deaconess Medical Center), Rosina T. Lis(Brigham and Women's Hospital), Xiaoqiu Wu(Harvard University), Edward C. Stack(Brigham and Women's Hospital), Massimo Loda(Brigham and Women's Hospital), Tao Liu(Dana-Farber Cancer Institute), Han Xu(Dana-Farber Cancer Institute), Laura Cato(Harvard University), James E. Thornton(Boston Children's Hospital), Richard I. Gregory(Boston Children's Hospital), Colm Morrissey(University of Washington Medical Center), Robert L. Vessella(University of Washington Medical Center), Rodolfo Montironi(Marche Polytechnic University), Cristina Magi‐Galluzzi(Cleveland Clinic), Philip W. Kantoff(Harvard University), Steven P. Balk(Beth Israel Deaconess Medical Center), X. Shirley Liu(Dana-Farber Cancer Institute), Myles Brown(Harvard University)
Science
December 13, 2012
10.1126/science.1227604
Cited by 879Open Access
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Abstract

Epigenetic regulators represent a promising new class of therapeutic targets for cancer. Enhancer of zeste homolog 2 (EZH2), a subunit of Polycomb repressive complex 2 (PRC2), silences gene expression via its histone methyltransferase activity. We found that the oncogenic function of EZH2 in cells of castration-resistant prostate cancer is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a coactivator for critical transcription factors including the androgen receptor. This functional switch is dependent on phosphorylation of EZH2 and requires an intact methyltransferase domain. Hence, targeting the non-PRC2 function of EZH2 may have therapeutic efficacy for treating metastatic, hormone-refractory prostate cancer.

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