EZH2 promotes CRPC growth by activating genes independent of its Polycomb function.

  • Major finding: EZH2 promotes CRPC growth by activating genes independent of its Polycomb function.

  • Mechanism: Phosphorylation switches EZH2 to a transcriptional coactivator of the androgen receptor.

  • Impact: Specific inhibition of EZH2-dependent gene activation may be beneficial in metastatic CRPC.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) inhibits gene expression as part of the Polycomb-repressive complex 2 (PRC2) via histone 3 lysine 27 trimethylation (H3K27me3) and has been implicated as an oncogene in various cancers. Elevated EZH2 expression is correlated with development of castration-resistant prostate cancer (CRPC), but the mechanisms by which EZH2 promotes disease progression are unclear. Xu and colleagues found that EZH2 was required for the growth of androgen-independent cancer cell lines and tumors, and EZH2 overexpression was sufficient to confer androgen independence. EZH2 depletion resulted in the downregulation of many genes that were highly expressed in hormone-refractory human prostate tumors and were associated with decreased survival, suggesting that EZH2 enhances prostate cancer progression by stimulating transcription. Indeed, in androgen-independent cells, EZH2 localized to a subset of promoters in the absence of H3K27me3 and promoted enrichment of active histone marks at these binding sites. The oncogenic effect of EZH2 on gene activation and CRPC growth was independent of other PRC2 subunits and required the catalytic methyltransferase activity of EZH2 and its interaction with the androgen receptor (AR) at AR binding motifs, indicating that EZH2 cooperates with the AR to induce gene expression in CRPC. This switch in EZH2 function from a transcriptional repressor to a coactivator was mediated by increased phosphorylation of EZH2 at serine-21 in androgen-independent cells, likely via AKT signaling; mutation of this residue to alanine prevented EZH2-driven gene activation and impaired androgen-independent growth. In addition, EZH2 serine-21 phosphorylation was increased in human CRPC samples compared with early-stage tumors, whereas H3K27me3 levels were reduced in CRPC. These results suggest that specific blockade of the transcriptional coactivator function of EZH2 may provide clinical benefit in patients with metastatic, hormone-refractory prostate cancer.

Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer is Polycomb-independent. Science 2012;338:1465–9.