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. Balk; X. Shirley Liu; Myles Brown

doi:10.1126/science.1227604

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

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683 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 language	English (US)
Pages (from-to)	1465-1469
Number of pages	5
Journal	Science
Volume	338
Issue number	6113
DOIs	https://doi.org/10.1126/science.1227604
State	Published - Dec 14 2012
Externally published	Yes

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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

Xu, K, Wu, ZJ, Groner, AC, He, HH, Cai, C, Lis, RT, Wu, X, Stack, EC, Loda, M, Liu, T, Xu, H, Cato, L, Thornton, JE, Gregory, RI, Morrissey, C, Vessella, RL, Montironi, R, Magi-Galluzzi, C, Kantoff, PW, Balk, SP, Liu, XS & Brown, M 2012, 'EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent', Science, vol. 338, no. 6113, pp. 1465-1469. https://doi.org/10.1126/science.1227604

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title = "EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent",

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.",

author = "Kexin Xu and Wu, {Zhenhua Jeremy} and Groner, {Anna C.} and He, {Housheng Hansen} and Changmeng Cai and Lis, {Rosina T.} and Xiaoqiu Wu and Stack, {Edward C.} and Massimo Loda and Tao Liu and Han Xu and Laura Cato and Thornton, {James E.} and Gregory, {Richard I.} and Colm Morrissey and Vessella, {Robert L.} and Rodolfo Montironi and Cristina Magi-Galluzzi and Kantoff, {Philip W.} and Balk, {Steven P.} and Liu, {X. Shirley} and Myles Brown",

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doi = "10.1126/science.1227604",

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AU - He, Housheng Hansen

AU - Cai, Changmeng

AU - Lis, Rosina T.

AU - Wu, Xiaoqiu

AU - Stack, Edward C.

AU - Loda, Massimo

AU - Liu, Tao

AU - Xu, Han

AU - Cato, Laura

AU - Thornton, James E.

AU - Gregory, Richard I.

AU - Morrissey, Colm

AU - Vessella, Robert L.

AU - Montironi, Rodolfo

AU - Magi-Galluzzi, Cristina

AU - Kantoff, Philip W.

AU - Balk, Steven P.

AU - Liu, X. Shirley

AU - Brown, Myles

PY - 2012/12/14

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

Abstract

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