RETRACTED: LncRNA HOTAIR regulates the expression of E-cadherin to affect nasopharyngeal carcinoma progression by recruiting histone methylase EZH2 to mediate H3K27 trimethylation
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HOTAIR
PRC2
Histone modifications are thought to control the regulation of genetic programs in normal physiology and cancer.Methylation (mono-, di-, and tri-methylation) on histone H3 lysine (K) 27 induces transcriptional repression, and thereby participates in controlling gene expression patterns.Enhancer of zeste (EZH) 2, a methyltransferase and component of the polycomb repressive complex 2 (PRC2), plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark.Abnormal EZH2 expression has been associated with various cancers including breast cancer.Here, we discuss the contribution of EZH2 and the PRC2 complex in controlling the H3K27 methylation status and subsequent consequences on genomic instability and the cell cycle in breast cancer cells.We also discuss distinct molecular mechanisms used by EZH2 to suppress BRCA1 functions.
PRC2
Histone Methylation
Cancer Epigenetics
Epigenomics
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Polycomb-repressive complex 2 (PRC2) is a histone methyltransferase that is critical for regulating transcriptional repression in mammals.Its catalytic subunit, EZH2, is responsible for the trimethylation of H3K27 and also undergoes automethylation.Using mass spectrometry analysis of recombinant human PRC2, we identified three methylated lysine residues (K510, K514, and K515) on a disordered but highly conserved loop of EZH2.Methylation of these lysines increases PRC2 histone methyltransferase activity, whereas their mutation decreases activity in vitro.De novo histone methylation in an EZH2 knockout cell line is greatly impeded by mutation of the automethylation lysines.EZH2 automethylation occurs intramolecularly (in cis) by methylation of a pseudosubstrate sequence on a flexible loop.This posttranslational modification and cis regulation of PRC2 are analogous to the activation of many protein kinases by autophosphorylation.We propose that EZH2 automethylation allows PRC2 to modulate its histone methyltransferase activity by sensing histone H3 tails, SAM concentration, and perhaps other effectors.
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Histone Methylation
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Polycomb-group proteins
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Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.
PRC2
Histone Methylation
Histone H4
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EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that methylates lysine 27 of histone 3. Overexpression of EZH2 has been found in a wide range of cancers, including those of the prostate and breast. In this review, we address the current understanding of the oncogenic role of EZH2, including its PRC2-dependent transcriptional repression and PRC2-independent gene activation. We also discuss the connections between EZH2 and other silencing enzymes, such as DNA methyltransferase and histone deacetylase. We comprehensively address the architecture of the PRC2 complex and the crucial roles of each subunit. Finally, we summarize new progress in developing EZH2 inhibitors, which could be a new epigenetic therapy for cancers.
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Recent studies have implicated that H3K9 lysine methyltransferases (KMTs) and polycomb repressive complex2 (PRC2) act in a cross-talk. However, a connection between GLP, one of the well-known H3K9 KMTs and the EZH2, one of the core members of PRC2, has not been established. Here we not only demonstrated that there was interaction between the GLP and the EZH2 proteins in vivo, but also provided evidence that the activity of EZH2 was effected by down-regulation of GLP. In light of these observations, western blotting, co-immunoprecipitation and qRT-PCR were performed to explore in GLP siRNA KGN cells. The specific interaction between GLP and EZH2 was demonstrated with co-immunoprecipitation. Our results also indicate that the decreased level of GLP participate in the modulation of EZH2 function in vivo.Taken together, our findings identified that an unanticipated interplay between the two histone lysine methyltransferases, which is implicated in regulating of a subset of developmental genes.
PRC2
Immunoprecipitation
Histone Methylation
Chromatin immunoprecipitation
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EZH2 methyltransferase is the subunit of the PRC2 complex that catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3). EZH2 is one of the Polycomb proteins that are the main epigenetic factors and are responsible for silencing and inactivating genes. This enzyme has a dual function in cancer - it is an oncogene and a suppressor gene. Abnormalities resulting from overexpression or mutation in EZH2 coding genes have been found in patients suffering from hematological malignancies and solid cancers. Therefore, it is necessary to treat these patients, has begun studies on molecules directed against the PRC2 complex, in particular against EZH1/EZH2. In 2012, a breakthrough in the development of targeted therapy with inhibitors of methyltransferase EZH2 has been the discovery of highly selective compounds containing the 2-pyridine in their chemical structure. In this review, draws attention to the latest findings regarding the oncogenic functions of EZH2 methyltransferase and their impact on the development of tumors. In addition, the text contains current information about preclinical and clinical trials on EZH2 inhibitors testing mainly in hematological cancers.
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The Polycomb group(PcG)protein family is a group of gene regulatory elements playing roles in embryonic development,which functioning in tow distinct protein complexes termed Polycomb-repressive complex 1(PRC1) and Polycomb-repressive complex 2(PRC2). EZH2 is the catalytic subunit of PRC2,which is a highly conserved histone methyltransferase that targets lysine-27 of histone H3. Most studies on human tumors show that EZH2 is over-expression in a variety of tumors,including prostate and breast. Although the mechanism of EZH2 with cancer progression is not determined,functional link between EZH2-mediated histone methylation and DNA methylation indicate which involved in the gene silencing machinery implicated in tumor suppressor loss. The authors review the basic molecular biology of EZH2 and the findings of EZH2 in different cancers. And also discuss EZH2 connections to other epigenetic modifying enzymes,as well as the consequences of EZH2 overabundance and its potential roles in tumorigenesis.
PRC2
Polycomb-group proteins
Histone Methylation
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Combining computational modeling, de novo compound synthesis, and in vitro and cellular assays, we have performed an inhibition study against the enhancer of zeste homolog 2 (EZH2) histone-lysine N-methyltransferase. This enzyme is an important catalytic component of the PRC2 complex whose alterations have been associated with different cancers. We introduce here several tambjamine-inspired derivatives with low micromolar in vitro activity that produce a significant decrease in histone 3 trimethylation levels in cancer cells. We demonstrate binding at the methyl transfer active site, showing, in addition, that the EZH2 isolated crystal structure is capable of being used in molecular screening studies. Altogether, this work provides a successful molecular model that will help in the identification of new specific EZH2 inhibitors and identify a novel class of tambjamine-derived EZH2 inhibitors with promising activities for their use in cancer treatment.
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PRC2
Polycomb-group proteins
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