Abstract
When assembled in multiprotein polycomb repressive complexes (PRCs), highly evolutionary conserved polycomb group (PcG) proteins epigenetically control gene activity. Although the composition of PRCs may vary considerably, it is well established that the embryonic ectoderm development (EED) 1, suppressor of zeste (SUZ) 12, and methyltransferase enhancer of zeste (EZH2)-containing complex, PRC2, which is abundant in highly proliferative cells (including cancer cells), establishes a repressive methylation mark on histone 3 (H3K27me3). From the perspective of molecular cancer pathogenesis, this effect, when directed towards a promoter of tumor suppressor genes, represents pro-tumorigenic effect. This mode of action was shown in several cancer models. However, EZH2 function extends beyond this scenario. The highly specific cellular background, related to the origin of cell and numerous external stimuli during a given time-window, may be the trigger for EZH2 interaction with other proteins, not necessarily histones. This is particularly relevant for cancer.This review provides a critical overview of the evolutional importance of PRC and discusses several important aspects of EZH2 functioning within PRC. The review also deals with mutational studies on EZH2. Due to the existence of several protein (and messenger RNA (mRNA)) isoforms, these mutations were stratified, using the protein sequence which is considered canonical. This approach showed that there is an urgent need for the uniformed positioning of currently known EZH2 mutations (somatic—in tumors, as well as germline mutations in the Weaver’s syndrome).Finally, we discuss EZH2 function with respect to amount of trimethylated H3K27, in a specific cellular milieu, through presenting the most recent data related to EZH2-H3K27m3 relationship in cancer. All these points are significant in considering EZH2 as a therapeutic target.
Highlights
Post-translational modifications (PTMs) of histone polypeptides contribute to the regulation of gene activity through establishing a specific epigenetic regulatory network [1]
These two proteins make a PRC2 together with a MES-3 protein which has no homolog in any other model organism, and such complex is involved in X-chromosome repression [10]; (4) Plants such as Arabidopsis thaliana, due to gene duplications, have three homologs of E(Z): CLF, MEA, SWN; three homologs of SU(Z)12: FIS, VRN2, EMF2; and five homologs of p55: MSI1-5, while only one homolog of extra sex combs (ESC) is present
Aberrant activity of PRC2 can result from aberrant enhancer of zeste homolog 2 (EZH2) expression, without chromosomal amplification, as a consequence of diverse aberrations which are present in cancer cells
Summary
Post-translational modifications (PTMs) of histone polypeptides contribute to the regulation of gene activity through establishing a specific epigenetic regulatory network [1]. As shown in gastric cancer, overexpressed lnc RNA 00152 needs to bind to EZH2 in order to exert oncogenic potential through recruiting the PRC2 to promoters of tumor suppressor (TS) genes p15 and p21 [24]. Aberrant activity of PRC2 can result from aberrant EZH2 expression, without chromosomal amplification, as a consequence of diverse aberrations which are present in cancer cells.
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