EZH2-Targeted Therapies in Cancer: Hype or a Reality

Abstract

Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as ARID1A, KDM6, and BAP1 are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.

Figure 1.. Aberration of EZH2 signaling in cancer.

EZH2 transcription is activated by transcription factors like E2F or ELK1. On the post-transcriptional level miR-101 and miR-26a have been shown to decrease EZH2 and therefore their down regulation also leads to EZH2 overexpression. Activity of EZH2 is regulated by AKT-mediated phosphorylation. C-myc leads to PTEN upregulation inhibiting the PI3K/AKT signaling pathway resulting a decreased inhibition of EZH2. Increased activity of EZH2 then leads to upregulated H3K27 methylation resulting in repression of tumor suppressor genes. This catalytic function is antagonized by NOTCH1. Non-catalytic or PRC2-independent roles for EZH2 include enhancing STAT3 activity, interaction with transcription factors, or stabilization of DDB promoting nucleotide excision repair.