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→Gene Overview
==Gene Overview==
==Gene Overview==
''EZH2'' (Enhancer of zeste homolog 2) encodes a histone-lysine N-methyltransferase which catalyses the addition of methyl groups to lysine 27 of histone H3 (H3K27) (Kuzmichev, 2002). EZH2 and its homolog EZH1 share four domains: homolog domain I, homolog domain II, a cysteine-rich domain, and the SET (Suppressor of variegation 3-9, Enhancer-of-zeste, and Trithorax) domain (reviewed in Li and Chen, 2015). EZH1 and EZH2 function through different mechanisms (Margueron et al., 2008). EZH2 is the enzymatic subunit of the Polycomb repressive complex 2 (PRC2), which also includes the core subunits EED, SUZ12, and RbAp46/48, although interactions with other proteins also occur (Margueron and Reinberg, 2011).
PRC2 is a highly conserved chromatin modification complex involved in transcriptional silencing of target loci through EZH2-catalysed H3K27 di- and trimethylation (H3K27m2 and H3K27m3), in some contexts with the aid of downstream Polycomb repressive complex 1 (PRC1) activity (Müller et al., 2002, reviewed in Margueron and Reinberg, 2011). Major targets of PRC2-mediated methylation are key developmental regulators that are inactive in undifferentiated cells but activated during differentiation in embryogenesis, and the EZH2/PRC complex has been implicated in maintenance of pluripotency in stem cells (Lee et al., 2006). Germline mutations in ''EZH2'' cause Weaver Syndrome, a rare congenital disorder characterised by overgrowth, advanced bone age, and distinctive skeletal and neurological abnormalities (Gibson et al., 2012).
''EZH2'' is important in hematopoesis where it preserves hematopoetic stem cell (HSC) potential, and overexpression of ''EZH2'' protects against cellular senescence during serial transplantation of stem cells (Kamminga et al., 2006). In lymphopoiesis ''EZH2'' is expressed strongly in proliferating cells including germinal center B cells, cycling T and B lymphocytes, and plasmablasts (reviewed in Good-Jacobson, 2014). Loss of ''EZH2'' abrogates germinal center formation (Béguelin et al., 2013).
''EZH2'' is overexpressed in cancerous cells from many tissues where ''EZH2'' expression would normally be low, and is universally associated with cancer progression (Bachmann et al., 2006; Bracken et al., 2003; Kleer et al., 2003; Varambally et al., 2002). Gain-of-function mutations affecting the ''EZH2'' SET catalytic domain, which spans residues 612-727 (NM_004456.4, UniProt), have been identified primarily in non-Hodgkin lymphomas (reviewed in Kim and Roberts, 2016). These mutations reduce the affinity of EZH2 for unmethylated and monomethylated H3K27 but increase affinity for the dimethylated version (Yap et al., 2011). Wild-type and mutant EZH2 then cooperate to drive hypertrimethylation of target loci (Sneeringer et al., 2010).
''EZH2'' appears to function as a tumour suppressor in myeloid disorders, as inactivating mutations have been identified in these contexts (Ernst et al., 2010; Nikoloski et al., 2010). These are typically truncating mutations or missense mutations in conserved residues within the catalytic or protein-interaction domains of EZH2 (Ernst et al., 2010).
Some studies have suggested that ''EZH2'' may also have oncogenic activating activity independent of PRC2, although this function is poorly defined. In prostate cancer this may be via a transactivator role for transcription factors including androgen receptor (Xu et al., 2012), while in breast cancer there is evidence ''EZH2'' is involved in activating NF-κB targets and ''NOTCH1'' while also participating in the estrogen receptor and Wnt signalling pathways (Gonzalez et al., 2014; Lee et al., 2011; Shi et al., 2007).
''EZH2'' can methylate non-histone targets, which may aid ubiquitin-mediated degradation of the methylated proteins, but the biological significance of this function is unclear (Lee et al., 2012).
MicroRNA-101 is a negative regulator of ''EZH2'', and ectopic expression of miR-101 in cell lines is able to suppress cell proliferation, invasiveness, and self-renewal (Konno et al., 2014; Luo et al., 2013). AKT-mediated phosphorylation of EZH2 at Ser21 (NM_004456.4) also suppresses methylation of H3K27 by impeding EZH2 binding to histone H3 (Cha et al., 2005).
Inhibitors of EZH2 have been developed and are in various stages of trial (reviewed in Kim and Roberts, 2016). Notably, tamazetostat has shown promise in phase I clinical trials and is undergoing phase II trials (Italiano et al., 2018).
==Common Alteration Types==
==Common Alteration Types==