Non-canonical functions of EZH2 in cancer

Abstract

Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2's canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis.

Keywords: EZH2; H3K27me3; cancer; non-canonical; oncogene; tumor suppressor.

Figure 1

Canonical and non-canonical functions of EZH2. (A) EZH2 functions as the methyltransferase domain of the PRC2 complex in cooperation with core components, EED, SUZ12 and RbAp46/48, to mediate methylation of lysine 27 on histone 3 (H3K27me3). Several accessory proteins that enhance and direct PRC2 function include JARID2, PCLs, AEBP2 among others. (B) In addition to methylating histone tails EZH2 can also methylate non-histone proteins, altering their function and activity with complicated effects on downstream gene expression. These include PLZF, RORα, GATA4, AR and STAT3. Post-translational modifications of EZH2 by AKT, JAK3, CDK1, and protein interactions with non-PRC2 proteins promote non-canonical functions, which can inhibit canonical PRC2 assembly and histone methylation. PRC2-independent functions of EZH2 include interactions with transcription factors such as RelA/B, CMYC, NMYC, STAT3, where they together function as transcriptional activators.