Polycomb-independent activity of EZH2 in castration resistant prostate cancer

Abstract

Epigenetic regulators represent a new class of therapeutic targets for cancer [1]. Substantial studies suggest that the enhancer of zeste homolog 2 (EZH2) is one of such pro-mising targets [2-4]. The current model of EZH2 onco-genic activity primarily focuses on its function as a subunit of Polycomb repressive complex 2 (PRC2), which silences gene expression via EZH2 histone methyltrans-ferase activity [5,6]. Using a genome-wide approach we found that the onco-genic function of EZH2 in castration resistant prostate cancer (CRPC) is independent of its role as a transcrip-tional repressor. Instead, it involves the ability of EZH2 to act as a co-activator for critical transcription factors including the androgen receptor (AR). This functional switch is dependent on phosphorylation of EZH2, and requires an intact methyltransferase domain. Given that the loss-of-function mutations of EZH2 were observed in myelodysplastic syndrome and acute leukemia [7,8], our discovery of the non-PRC2 function of EZH2 in CRPC raises the potential to develop inhibitors that specifically target the EZH2 activation function while sparing its PRC2 repressive function to avoid the potential hematolo-gic side effects. In addition, our finding that EZH2 coop-erates with AR-associated complexes and requires phosphorylation to support CRPC growth suggests novel combination therapies for the treatment of metastatic, hormone-refractory prostate cancer.