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

Kexin Xu, Zhenhua Jeremy Wu, Anna C. Groner, Housheng Hansen He, Changmeng Cai, Rosina T. Lis, Xiaoqiu Wu, Edward C. Stack, Massimo Loda, Tao 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. BalkX. Shirley Liu, Myles Brown

Research output: Contribution to journalArticle

455 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1465-1469
Number of pages5
JournalScience
Volume338
Issue number6113
DOIs
StatePublished - Dec 14 2012
Externally publishedYes

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    Xu, K., Wu, Z. J., Groner, A. C., He, H. H., Cai, C., Lis, R. T., Wu, X., Stack, E. C., Loda, M., Liu, T., Xu, H., Cato, L., Thornton, J. E., Gregory, R. I., Morrissey, C., Vessella, R. L., Montironi, R., Magi-Galluzzi, C., Kantoff, P. W., ... Brown, M. (2012). EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent. Science, 338(6113), 1465-1469. https://doi.org/10.1126/science.1227604