title: Polycomb repressive complex's evolutionary conserved function: the role of EZH2 status and cellular background.
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.
authors.affiliation: Division of Molecular Medicine, Laboratory for Epigenomics, Rudjer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia.
authors.forename: Koraljka
authors.initials: K
authors.lastname: Gall Trošelj
authors.affiliation: Division of Molecular Medicine, Laboratory for Epigenomics, Rudjer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia.
authors.forename: Renata
authors.initials: R
authors.lastname: Novak Kujundzic
authors.affiliation: Division of Molecular Biology, Laboratory for Evolutionary Genetics, Rudjer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia.
authors.forename: Djurdjica
authors.initials: D
authors.lastname: Ugarkovic
mesh_terms: D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: Cancer; EZH2; Evolution; H3K27me3; Mutation; Polycomb repressive complexes 1–4