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

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 o...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2012-12, Vol.338 (6113), p.1465-1469
Main Authors: Xu, Kexin, Wu, Zhenhua Jeremy, Groner, Anna C., He, Housheng Hansen, Cai, Changmeng, Lis, Rosina T., Wu, Xiaoqiu, Stack, Edward C., Loda, Massimo, Liu, Tao, Xu, Han, Cato, Laura, Thornton, James E., Gregory, Richard I., Morrissey, Colm, Vessella, Robert L., Montironi, Rodolfo, Magi-Galluzzi, Cristina, Kantoff, Philip W., Balk, Steven P., Liu, X. Shirley, Brown, Myles
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Castration
Cell growth
Cell Line, Tumor
Cell lines
Cell nucleus
Cellular immunity
Cohort Studies
Enhancer of Zeste Homolog 2 Protein
Epigenetics
Gene expression
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes
Gynecology. Andrology. Obstetrics
Humans
Jumonji Domain-Containing Histone Demethylases - metabolism
Male
Male genital diseases
Medical sciences
Methyltransferases - chemistry
Methyltransferases - genetics
Methyltransferases - metabolism
Mice
Mice, Inbred ICR
Mice, SCID
Nephrology. Urinary tract diseases
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Oncology
Pheromones
Phosphorylation
Polycomb Repressive Complex 2 - genetics
Polycomb Repressive Complex 2 - metabolism
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - mortality
Protein Structure, Tertiary
Receptors, Androgen - metabolism
Stem cells
Tumors
Tumors of the urinary system
Urinary tract. Prostate gland
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1227604