EZH2: not EZHY (easy) to deal

Abstract

Seminal discoveries have established that epigenetic modifications are important for driving tumor progression. Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain, by posttranslational modification of histones, the silenced state of genes involved in critical biologic processes, including cellular development, stem cell plasticity, and tumor progression. PcG proteins are found in two multimeric protein complexes called Polycomb repressive complexes: PRC1 and PRC2. Enhancer of zeste homolog 2 (EZH2), catalytic core subunit of PRC2, epigenetically silences several tumor-suppressor genes by catalyzing the trimethylation of histone H3 at lysine 27, which serves as a docking site for DNA methyltransferases and histone deacetylases. Evidence suggests that overexpression of EZH2 is strongly associated with cancer progression and poor outcome in disparate cancers, including hematologic and epithelial malignancies. The regulatory circuit and molecular cues causing EZH2 deregulation vary in different cancer types. Therefore, this review provides a comprehensive overview on the oncogenic role of EZH2 during tumorigenesis and highlights the multifaceted role of EZH2, as either a transcriptional activator or repressor depending on the cellular context. Additional insight is provided on the recent understanding of the causes and consequences of EZH2 overexpression in specific cancer types. Finally, evidence is discussed on how EZH2 has emerged as a promising target in anticancer therapy and the prospects for targeting EZH2 without affecting global methylation status. Thus, a better understanding of the complex epigenetic regulatory network controlling EZH2 expression and target genes facilitates the design of novel therapeutic interventions.

Figure 1. Epigenetic crosstalk showing functional link between PcG proteins (PRC1 and PRC2), histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) during transcriptional silencing of a PRC2 target gene

Initial deacetylation of histone H3 acetylated at Lysine 27 (H3K27Ac) by HDACs allows the catalysis of trimethylation of Lysine 27 (H3K27me3) by EZH2 containing PRC2 complex. H3K27me3 enrichment facilitate the binding of PRC1 complex that catalyze the mono-ubiquitylation of histone 2A at lysine 119 (H2AK119ub) and may also serve as a docking site for DNMTs which methylate CpG islands in the promoter region. Methylated CpG islands are then bound by a group of proteins possessing methyl DNA binding characteristics such as methyl CpG binding protein 2 (MeCP2), methyl CpG binding domain protein 1 (MBD1), which form a part of other histone modifying complexes like NURD and Sin3A. These events assist in the recruitment of HDACs and histone methyltransferase-containing protein complexes, contributing further to target gene repression. H3K27me3 and occupancy of target promoter by other histone modifying proteins lead to the formation of highly compressed chromatin structure which is inaccessible to RNA Pol II causing transcriptional silencing of target gene.