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Review
. 2016 May 27;8:55.
doi: 10.1186/s13148-016-0226-1. eCollection 2016.

Polycomb Repressive Complex's Evolutionary Conserved Function: The Role of EZH2 Status and Cellular Background

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Free PMC article
Review

Polycomb Repressive Complex's Evolutionary Conserved Function: The Role of EZH2 Status and Cellular Background

Koraljka Gall Trošelj et al. Clin Epigenetics. .
Free PMC article

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.

Keywords: Cancer; EZH2; Evolution; H3K27me3; Mutation; Polycomb repressive complexes 1–4.

Figures

Fig. 1
Fig. 1
Association of PRC-EZH2 complexes with different EED isoforms in the presence (H1+) or absence (H1−) of linker histone H1 directs EZH2-mediated methylation towards H3K27 or H1K26. PRC2, which contains the longest form of EED (EED1), is able to methylate isolated histone H3. When targeted to oligonucleosomes containing linker histone H1, PRC2 methylates histone H1 rather than histone H3. PRC3, containing EED3 and EED4, methylates nucleosomal histone H3, but its methyltransferase activity is inhibited by histone H1. PRC4, containing EED2 and NAD-dependent deacetylase SIRT1, methylates histone H1 when present, but has also low methylating capacity towards H3K27 in the absence of histone H1 (depicted in gray) [13, 14]
Fig. 2
Fig. 2
Alignment of five EZH2 isoforms protein sequences (UniProt). SET domain is shown in green (Q15910-1 AA 612–727; Q15910-2 AA 617–732; Q15910-3 AA 573–688; Q15910-4 AA 603–718; Q15910-5 AA 561–676). Germline mutations [27] are shown in orange, “loss of function” mutations [42] in blue, and “gain of function” mutations [26, 30, 32, 33, 44] in red. All mutations listed in the cited references are marked on respective isoform sequences, highlighting the lack of uniformity in annotating mutations according to consensus sequence (Q15910-1). Therefore, mutation A677 (in isoform 1) is listed as somatic, activating mutation and at the same time, annotated as mutation A682 (in isoform 2), has been listed as germline mutation which was discovered in the Weaver syndrome patient who developed ALL and neuroblastoma in early childhood. This is in accord with the oncogenic potential of this mutation. Inactivating mutations R684 in isoform 2 (corresponding to R679 in isoform 1) and E745 in isoform 2 (corresponding to E740 in isoform 1) have been shown to be mutated in Weaver syndrome patients. None of the five patients with inherited mutation R684C (present as somatic mutation in one 82-year-old patient suffering from chronic myelomonocytic leukemia) developed malignant disease at the time of testing for germline mutation of EZH2. Germline mutation E745K (isoform 2) was present in a patient who developed non-Hodgkins lymphoma at the age of 13. Somatic mutation of this codon was detected in one patient with chronic myeloic leukemia during blast crisis.

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