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

Abstract

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. Here we report that the oncogenic function of EZH2 in castration-resistant prostate cancer (CRPC) is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a co-activator for critical transcription factors including the androgen receptor (AR). 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 significant therapeutic efficacy for treating metastatic, hormone-refractory prostate cancer.

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

“…It is important to note that this effect of EZH2 acting through FOXM1 was independent of the catalytic activity of PRC2 on H3K27me3, as is consistent with growing reports that EZH2 has non-PRC2 roles usually associated with transcriptional activation (8)(9)(10)(11)(12)(13). Paradoxically, Ezh2 also complexes with Suz12 and Eed to suppress MMP promoters directly, providing a predominant tumor-suppressor mechanism by inhibiting the expression of MMPs in normoxia.…”

“…In multiple malignancies including breast cancer, the up-regulation of Ezh2 is positively correlated with tumor grade, metastasis propensity, and poor survival rate (7). The oncogenic function of Ezh2 has been linked to both PRC2-dependent and PRC2-independent activities (8)(9)(10)(11)(12)(13). Paradoxically, a context-dependent tumor-suppressive function of Ezh2 or PRC2 also has been reported in several malignancies (14)(15)(16)(17)(18).…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…However, as these studies must be performed on pooled cells, it is important to consider that mixed or bivalent marks at given loci may also represent heterogeneity in cell populations or even allelic variability within cells 11 . Importantly, the activities of chromatin-modifying enzymes are responsive to changes in the environment, exhibiting direct links to cytokine, metabolic and kinase signalling pathways 152,[160][161][162] (FIG. 2).…”

Au cœur d’une complexité biologique

“…Le nouveau modèle hiérarchique proposé par Blackledge et al [19] [27]. EZH2 fonctionne également comme un activateur transcriptionnel, dans les cancers de la prostate résistants à la castration [28], ou dans les lymphomes de cellules NKT (natural killer T) [29]. Dans ces deux pathologies, c'est la forme phosphorylée d'EZH2 qui est impliquée dans ses fonctions activatrices [28].…”

“…EZH2 fonctionne également comme un activateur transcriptionnel, dans les cancers de la prostate résistants à la castration [28], ou dans les lymphomes de cellules NKT (natural killer T) [29]. Dans ces deux pathologies, c'est la forme phosphorylée d'EZH2 qui est impliquée dans ses fonctions activatrices [28]. Dans le cancer de la prostate, certains gènes cibles d'EZH2 sont associés à la marque activatrice H3K4me3 et à la présence de l'ARN polymérase II.…”