Abstract
Enhancer of zeste homolog 2 (EZH2) plays critical roles in a range of biological processes including organ development and homeostasis, epigenomic and transcriptomic regulation, gene repression and imprinting, and DNA damage repair. A widely known function of EZH2 is to serve as an enzymatic subunit of Polycomb repressive complex 2 (PRC2) and catalyze trimethylation of histone H3 lysine 27 (H3K27me3) for repressing target gene expression. However, an increasing body of evidence demonstrates that EZH2 has many “non-conventional” functions that go beyond H3K27 methylation as a Polycomb factor. First, EZH2 can methylate a number of nonhistone proteins, thereby regulating cellular processes in an H3K27me3-independent fashion. Furthermore, EZH2 relies on both methyltransferase-dependent and methyltransferase-independent mechanisms for modulating gene-expression programs and/or epigenomic patterns of cells. Importantly, independent of PRC2, EZH2 also forms physical interactions with a number of DNA-binding factors and transcriptional coactivators to context-dependently influence gene expression. The purpose of this review is to detail the complex, noncanonical roles of EZH2, which are generally less appreciated in gene and (epi)genome regulation. Because EZH2 deregulation is prevalent in human diseases such as cancer, there is increased dependency on its noncanonical function, which shall have important implications in developing more effective therapeutics.
Highlights
Polycomb group (PcG) genes were initially identified as regulator of body segmentation and repressor of Hox gene expression in Drosophila and were subsequently shown to be conserved among other organisms such as mammal
It is well established that enhancer of zeste homolog 2 (EZH2)/1 functions as Polycomb repressive complex 2 (PRC2)’s catalytic subunit to repress gene transcription at least partly through inducing trimethylation of histone H3 lysine 27 (H3K27me3), a chromatin mark that can serve as a docking site for recruiting “effector/reader” proteins
In the Estrogen Receptor (ER)-negative basal-like breast cancer cells, EZH2 interacts with RelA and RelB (Figure 3a and Table 2), two core subunits of NF-κB, and functions as NF-κB coactivator independent of its histone methyltransferase activity [70]; this role of EZH2 in promoting NF-κB signaling was in agreement with the EZH2-mediated transcriptional activation of RelB, again through a methyltransferase-independent mechanism, to sustain the self-renewal and tumor-initiating phenotypes of TNBC cells [30]
Summary
Polycomb group (PcG) genes were initially identified as regulator of body segmentation and repressor of Hox gene expression in Drosophila and were subsequently shown to be conserved among other organisms such as mammal. Biochemical charactarizations of Polycomb repressive complexes 2 and 1 (PRC2 and PRC1) revealed their specific histone-modifying activities (Figure 1) [1,2,3,4,5,6,7,8]. It is well established that EZH2/1 functions as PRC2’s catalytic subunit to repress gene transcription at least partly through inducing trimethylation of histone H3 lysine 27 (H3K27me3), a chromatin mark that can serve as a docking site for recruiting “effector/reader” proteins. It is conceivable that an increased level of EZH2 may promote “nonconventional” protein–protein interactions unrelated to PRC2. Cellular contexts such as kinase signaling may profoundly alter PRC2 functionality. We will discuss about nonhistone methylation and noncanonical effects by EZH2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
