Targeting EZH2 in cancer

Abstract

Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

Figure 1. The PRC2 complex and its function in transcriptional regulation

a. The mammalian PRC2 complex consists of four core subunits: the catalytic subunit enhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and retinoblastoma (Rb)-associated protein 46/48 (RbAp46/48) and additional proteins, including AEBP2, PCL, and JARID2 have also at times been found to be associating with PRC2 complex to modulate the activity of PRC2 in different context. b. EZH2 regulates transcriptional activity: 1) EZH2 is also capable of methylating a number of non-histone protein substrates, 2) PRC2 methylates Histone 3 on lysine 27, which contributes to transcriptional silencing, 3) EZH2 also has a PRC2-independent role in transcriptional activation.

Figure 2. EZH2 as a therapeutic target in cancer

a. The roles of EZH2 mediated transcriptional silencing are context specific. For cell types in which its hyperactivity drives oncogenesis, contributions from silencing of lineage specification genes, the tumor suppressor Rb and DNA repair genes have been identified. b. Cancers harboring SWI/SNF mutations and gain-of-function EZH2 mutations confer dependency on EZH2 inhibition. Early pre-clinical evidence suggests potential benefit of combination therapy with an EZH2 inhibitor. At least in the case of cancers driven by SWI/SNF mutation, Ras pathway mutations can confer resistance to EZH2 inhibition.