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.
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kexin
authors.initials: K
authors.lastname: Xu
authors.forename: Zhenhua Jeremy
authors.initials: ZJ
authors.lastname: Wu
authors.forename: Anna C
authors.initials: AC
authors.lastname: Groner
authors.forename: Housheng Hansen
authors.initials: HH
authors.lastname: He
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.forename: Rosina T
authors.initials: RT
authors.lastname: Lis
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Wu
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.forename: Laura
authors.initials: L
authors.lastname: Cato
authors.forename: James E
authors.initials: JE
authors.lastname: Thornton
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Montironi
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D015331:Cohort Studies; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D015513:Oncogene Proteins; D011944:Receptors, Androgen; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2