Journal
SCIENCE
Volume 338, Issue 6113, Pages 1465-1469Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1227604
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Funding
- Prostate Cancer Foundation (PCF)
- Swiss National Science Foundation
- NSF
- A. David Mazzone Project Development Award
- PCF Challenge Awards
- U.S. Department of Defense Idea Development Award [PC100950]
- National Cancer Institute [CA131945, CA89021, CA90381]
- NIH [CA166507, CA111803, CA090381, GM99409, CA85859, CA097186]
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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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