Re: EZH2 oncogenic activity in castration-resistant prostate cancer cells is polycomb-independent

摘要

The authors show in this study that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a polycomb repressor to a transcriptional coactivator of the androgen receptor. Rescue experiments and the lack of correlation with H3K27me3 levels support a role for EZH2 directed methylation of substrates other than H3K27, including potential nonhistone proteins. The finding of an altered function for EZH2 in CRPC cells raises the potential to develop inhibitors that specifically target the EZH2 activation function while sparing its PRC2 repressive function. In addition, the finding that EZH2 cooperates with androgen receptor associated complexes and requires phosphorylation to support CRPC growth suggests the possibility of novel combination therapies for the treatment of metastatic, hormone refractory prostate cancer.