Findings Suggest New Approach for Treating Castration Resistant Prostate Cancer

Attacking one function of the epigenetic regulator protein EZH2 (enhancer of zeste homolog 2) may be a way to resensitize prostate cancer cells that have developed resistance to male hormone suppression.

EZH2 levels are known to be dramatically increased in late-stage castration resistant prostate cancer (CRPC). This protein, which is a subunit of the Polycomb repressive complex 2 (PRC2), silences gene expression via its histone methyltransferase activity. However, in a paper published in the December 14, 2012, issue of the journal Science, investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) reported the discovery of another role for EZH2 in prostate cancer cells.

They found that the oncogenic function of EZH2 in CRPC cells was independent of its role as a transcriptional repressor. Instead, it involved the ability of EZH2 to act as a coactivator for critical transcription factors including the androgen receptor. This functional switch was dependent on phosphorylation of EZH2 and required an intact methyltransferase domain.

Drugs that target EHH2's ability to block gene transcription are being tested. “But we found that is not the important function of EZH2 in CRPC,” said senior author Dr. Myles Brown, professor of medicine at the Dana Farber Cancer Institute. “In these cancers, EZH2 works with the androgen receptor to turn on genes involved with cell growth.” Therefore, inhibitors of EZH2 that avoid targeting its gene-repressor function might be a safe and effective strategy for use in CRPC.

Another approach would be to target the PI3 kinase (PI3K) molecular signaling pathway, which activates the EZH2 protein. Several PI3K inhibitors are in clinical trials at present, and Dr. Brown said, “A combination of drugs to inhibit both that pathway and the EZH2 protein might be yet another way to attack the resistant prostate cancers.”

Related Links:
Dana-Farber Cancer Institute