Histone Methyltransferase EZH2 Is Transcriptionally Induced by Estradiol as Well as Estrogenic Endocrine Disruptors Bisphenol-A and Diethylstilbestrol

Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I.; Bobzean, Samara A.M.; Perrotti, Linda I.; Mandal, Subhrangsu S.

doi:10.1016/j.jmb.2014.07.025

Cited by 106 publications

(79 citation statements)

References 96 publications

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“…For BPA, it has been reported that activated ER␣ can associate to estrogen-responsive elements that are present in the promoter of the histone modifying methyltransferase EZH2. This binding of ER␣ to estrogen-responsive elements attracts other coregulators, such as the histone modifying enzymes that acetylate and methylate histone tails, both resulting in an activated chromatin state and eventual expression of EZH2 that can then result in elevated levels of H3K27 trimethylation, potentially affecting global epigenetic gene regulation (29,30). Thus, although most of the present environmental obesogen research focuses on PPAR␥ as the main target of obesogens, it is likely that other mechanisms, including the activation of other steroid hormone receptors, are involved as well.…”

Section: Edc Mechanisms Of Action In Obesitymentioning

confidence: 99%

The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals

Stel

Legler

2015

Endocrinology

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Recent research supports a role for exposure to endocrine-disrupting chemicals (EDCs) in the global obesity epidemic. Obesogenic EDCs have the potential to inappropriately stimulate adipogenesis and fat storage, influence metabolism and energy balance and increase susceptibility to obesity. Developmental exposure to obesogenic EDCs is proposed to interfere with epigenetic programming of gene regulation, partly by activation of nuclear receptors, thereby influencing the risk of obesity later in life. The goal of this minireview is to briefly describe the epigenetic mechanisms underlying developmental plasticity and to evaluate the evidence of a mechanistic link between altered epigenetic gene regulation by early life EDC exposure and latent onset of obesity. We summarize the results of recent in vitro, in vivo, and transgenerational studies, which clearly show that the obesogenic effects of EDCs such as tributyltin, brominated diphenyl ether 47, and polycyclic aromatic hydrocarbons are mediated by the activation and associated altered methylation of peroxisome proliferator-activated receptor-γ, the master regulator of adipogenesis, or its target genes. Importantly, studies are emerging that assess the effects of EDCs on the interplay between DNA methylation and histone modifications in altered chromatin structure. These types of studies coupled with genome-wide rather than gene-specific analyses are needed to improve mechanistic understanding of epigenetic changes by EDC exposure. Current advances in the field of epigenomics have led to the first potential epigenetic markers for obesity that can be detected at birth, providing an important basis to determine the effects of developmental exposure to obesogenic EDCs in humans.

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Section: Edc Mechanisms Of Action In Obesitymentioning

confidence: 99%

The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals

Stel

Legler

2015

Endocrinology

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“…The regulation and function of EZH2 as well as the development of EZH2 inhibitors and EZH2-targeted therapy based on synthetic lethal strategy will be described below, and perspectives on EZH2-related pathophysiology and EZH2-targeted therapy will also be provided. 10 [59][60][61] (Figure 2A). EZH2 mRNA is transcriptionally repressed directly by NFIB [62] and indirectly via the TP53-CDKN1A axis [63] and is also post-transcriptionally repressed by miRNAs, such as miR-25, miR-26a, miR-30d, miR-98, miR-101 and miR-214 (Figure 2A) [64][65][66].…”

Section: Ezh2 Mll3 and Nsds As Rational Drug Targetsmentioning

confidence: 99%

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

Katoh

2015

Epigenomics

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Germline mutations in canonical SET-methyltransferases have been identified in autism and intellectual disability syndromes and gain-of-function somatic alterations in EZH2, MLL3, NSD1, WHSC1 (NSD2) and WHSC1L1 (NSD3) in cancer. EZH2 interacts with AR, ERα, β-catenin, FOXP3, NF-κB, PRC2, REST and SNAI2, resulting in context-dependent transcriptional activation and repression. Pharmacological EZH2 inhibitors are currently in clinical trials for the treatment of B-cell lymphomas and solid tumors. EZH2 inhibitors might also be applicable in the treatment of SWI/SNF-mutant cancers, reflecting the reciprocal expression of and functional overlap between EZH2 and SMARCA4. Because of the risks for autoimmune diseases, cognitive impairment, cardiomyopathy and myelodysplastic syndrome, EZH2 inhibitors should be utilized for cancer treatment in patients receiving long-term surveillance but not for cancer chemoprevention.

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“…The enhancer of zeste homolog 2 (EZH2) is a methyltransferase which catalyzes methylation of lysine 27 in histone H3 resulting in suppression of target gene expression (23). The histone demethylase JMJD3 opposes the activity of EZH2 by demethylating histone H3 lysine 27.…”

Section: Introductionmentioning

confidence: 99%

The histone methyltransferase EZH2 promotes mammary stem and luminal progenitor cell expansion, metastasis and inhibits estrogen receptor-positive cellular differentiation in a model of basal breast cancer

Crowe

2015

Oncology Reports

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Abstract. Mammary stem cells (MSCs) are the progenitor population for human breast epithelia. MSCs give rise during mammary gland development to estrogen receptor (ER)-negative basal cells and the ER -luminal progenitor (LP) population which maintains ER + and ER -luminal cells. The MSC population is expanded and tumorigenic in some mouse mammary cancer models, and these tumor-initiating cells have been isolated from human breast cancers. MSC expansion is associated with aggressive biological behavior in human breast cancer. The LP population is tumorigenic in some mouse mammary cancer models, and is the progenitor population of basal breast cancer in humans. The enhancer of zeste homolog 2 (EZH2) is a methyltransferase which catalyzes lysine 27 methylation in histone H3 resulting in suppression of target gene expression. The histone demethylase JMJD3 opposes the activity of EZH2 by demethylating histone H3 lysine 27. EZH2 is a member of the polycomb group of proteins which regulates cell type identity. EZH2 expression was found to be increased in histologically normal human breast tissue among women with high breast cancer risk, and was elevated in ductal hyperplasia and ductal carcinoma in situ. EZH2 overexpression is associated with poorly differentiated and aggressive breast cancer in humans. However, the mechanisms by which EZH2 results in increased breast cancer risk and aggressive tumors are not completely characterized. Using in vivo transplantation of mammary cancer stem cells transduced with EZH2 or JMJD3 shRNAs, we demonstrated that EZH2 promotes mammary stem and LP cell expansion, metastasis and inhibits ER-positive cellular differentiation.

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Histone Methyltransferase EZH2 Is Transcriptionally Induced by Estradiol as Well as Estrogenic Endocrine Disruptors Bisphenol-A and Diethylstilbestrol

Cited by 106 publications

References 96 publications

The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals

The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

The histone methyltransferase EZH2 promotes mammary stem and luminal progenitor cell expansion, metastasis and inhibits estrogen receptor-positive cellular differentiation in a model of basal breast cancer

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