EZH2 Oncogenic Activity in Castration Resistant Prostate Cancer Cells is Polycomb-Independent

By Kexin Xu, Z. Wu, A. Groner, H. He, Changmeng Cai, R. Lis, Xiaoqiu Wu, Edward C. Stack, M. Loda, Tao Liu and 12 more. Science, 2012

852 citations recorded by the source corpus.

Alternative Role for EZH2 Epigenetic regulators are implicated in cancer progression and proposed as therapeutic targets. Xu et al. (p. 1465; see the Perspective by Cavalli) report that EZH2 (Enhancer of zeste homolog 2), a factor previously thought to exert its oncogenic function primarily as part of the polycomb repressive complex, acts through a distinct mechanism in cells of castration-resistant prostate cancer. Rather than exclusively silencing gene expression through histone methylation, EZH2 acts as a transcriptional coactivator. The activation function of EZH2 plays a critical role in the growth of castration-resistant prostate cancer cells, which could be relevant in future drug development. An epigenetic regulator positively regulates gene expression in cell-based models of hormone-resistant prostate cancer. Epigenetic regulators represent a promising new class of therapeutic targets for cancer. Enhancer of zeste homolog 2 (EZH2), a subunit of Polycomb repressive complex 2 (PRC2), silences gene expression via its histone methyltransferase activity. We found that the oncogenic function of EZH2 in cells of castration-resistant prostate cancer is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a coactivator for critical transcription factors including the androgen receptor. This functional switch is dependent on phosphorylation of EZH2 and requires an intact methyltransferase domain. Hence, targeting the non-PRC2 function of EZH2 may have therapeutic efficacy for treating metastatic, hormone-refractory prostate cancer.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3ce5064b3eae7a73fe2680efebd265a95da52cc0

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Citations in the corpus

Genetics and biology of prostate cancer (2018, background): “…loci (Yeager et al. 2007; Eeles et al. 2008, 2009, 2013; Thomas et al. 2008;Gudmundsson et al. 2009; Yeager et al. 2009; Takata et al. 2010; Xu et al. 2012a; Schumacher et al. 2018), such as the risk-associated single-nucleotide polymorphism (SNP) rs339331 that increases expression of the…”
Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells (2013, background): “…Cancer Cell 23, 1–14, June 10, 2013 ª2013 Elsevier Inc. studies to decipher underlying molecular mechanisms are warranted as a recent study reported EZH2 S21 phosphorylation as a critical modification for EZH2 to function as a transcriptional co-activator with androgen receptor (Xu et al., 2012).”