EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent
- Kexin Xu
- Zhenhua J. Wu
- Anna C. Groner
- Housheng Hansen He
- Changmeng Cai
- Rosina T. Lis
- Xiaoqiu Wu
- Edward C. Stack
- Massimo Loda
- TLTao Liu
- Han Xu
- Laura Cato
- James E. Thornton
- Richard I. Gregory
- Colm Morrissey
- Robert L. Vessella
- Rodolfo Montironi
- Cristina Magi‐Galluzzi
- Philip W. Kantoff
- Steven P. Balk
- X. Shirley Liu
- Myles Brown
- TLTao Liu
Science · 2012 · American Association for the Advancement of Science
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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.