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. Balk

X. Shirley Liu, Myles Brown

Biochemistry

University at Buffalo

Dana-Farber Cancer Institute
Harvard University
Beth Israel Deaconess Medical Center
Brigham and Women’s Hospital
King's College London
Boston Children's Hospital
University of Washington
Puget Sound VA Health Care System
Marche Polytechnic University
Cleveland Clinic Foundation

Research output: Contribution to journal › Article › peer-review

782 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
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

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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

@article{e30f9997717d44ffb00e2bfdebd09273,

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",

year = "2012",

month = dec,

day = "14",

doi = "10.1126/science.1227604",

language = "English",

volume = "338",

pages = "1465--1469",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6113",

}

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

TY - JOUR

T1 - EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent

AU - Xu, Kexin

AU - Wu, Zhenhua Jeremy

AU - Groner, Anna C.

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

Y1 - 2012/12/14

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/84871052080

U2 - 10.1126/science.1227604

DO - 10.1126/science.1227604

M3 - Article

C2 - 23239736

SN - 0036-8075

VL - 338

SP - 1465

EP - 1469

JO - Science

JF - Science

IS - 6113

ER -

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

Abstract

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