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EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent

Kexin Xu1, Zhenhua Jeremy Wu, Anna C Groner

  • 1Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Science (New York, N.Y.)
|December 15, 2012
PubMed

Insights

Enhancer of zeste homolog 2 (EZH2) drives castration-resistant prostate cancer by coactivating transcription factors, not just gene silencing. Targeting this non-PRC2 function offers new therapeutic strategies for advanced prostate cancer.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epigenetic regulators are emerging as key cancer therapeutic targets.
  • Enhancer of zeste homolog 2 (EZH2), a component of Polycomb repressive complex 2 (PRC2), typically functions in gene silencing through histone methylation.
  • Castration-resistant prostate cancer (CRPC) presents a significant therapeutic challenge.

Purpose of the Study:

  • To investigate the oncogenic role of EZH2 in castration-resistant prostate cancer.
  • To determine if EZH2's function in CRPC relies on its canonical transcriptional repressor activity.
  • To explore novel therapeutic strategies targeting EZH2 in advanced prostate cancer.

Main Methods:

  • Analysis of EZH2 function in castration-resistant prostate cancer cell lines.
  • Investigating the interaction of EZH2 with transcription factors, including the androgen receptor.
  • Assessing the impact of EZH2 phosphorylation and methyltransferase activity on its oncogenic function.

Main Results:

  • EZH2 promotes castration-resistant prostate cancer progression through a mechanism independent of its transcriptional repressor function.
  • EZH2 acts as a coactivator for key transcription factors, notably the androgen receptor.
  • This coactivator function is contingent upon EZH2 phosphorylation and requires an intact methyltransferase domain.

Conclusions:

  • The oncogenic activity of EZH2 in CRPC involves a non-canonical role as a coactivator.
  • Targeting the non-PRC2, coactivator function of EZH2 presents a promising therapeutic avenue.
  • This approach may be effective for treating metastatic, hormone-refractory prostate cancer.

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