title: Histone methyltransferase EZH2 is transcriptionally induced by estradiol as well as estrogenic endocrine disruptors bisphenol-A and diethylstilbestrol.
abstract: Enhancer of Zeste homolog 2 (EZH2), a methyltransferase specific to histone 3 lysine 27, is a critical player in gene silencing and is overexpressed in breast cancer. Our studies demonstrate that EZH2 is transcriptionally induced by estradiol in cultured breast cancer cells and in the mammary glands of ovariectomized rats. EZH2 promoter contains multiple functional estrogen-response elements. Estrogen receptors (ERs) and ER coregulators such as mixed lineage leukemia (MLL) histone methylases (MLL2 and MLL3) and histone acetyltransferase CBP/P300 bind to the EZH2 promoter in the presence of estradiol and regulate estradiol-induced EZH2 expression. EZH2 expression is also increased upon exposure to estrogenic endocrine disrupting chemicals (EDCs) such as bisphenol-A (BPA) and diethylstilbestrol (DES). Similar to estradiol, BPA and DES-induced EZH2 expression is coordinated by ERs, MLLs and CBP/P300. In summary, we demonstrate that EZH2 is transcriptionally regulated by estradiol in vitro and in vivo, and its expression is potentially dysregulated upon exposure to estrogenic EDCs.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Arunoday
authors.initials: A
authors.lastname: Bhan
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Imran
authors.initials: I
authors.lastname: Hussain
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Khairul I
authors.initials: KI
authors.lastname: Ansari
authors.affiliation: Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Samara A M
authors.initials: SA
authors.lastname: Bobzean
authors.affiliation: Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Linda I
authors.initials: LI
authors.lastname: Perrotti
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA. Electronic address: smandal@uta.edu.
authors.forename: Subhrangsu S
authors.initials: SS
authors.lastname: Mandal
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004054:Diethylstilbestrol / Q000494:pharmacology*; D052244:Endocrine Disruptors / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy; D010636:Phenols / Q000494:pharmacology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004268:DNA-Binding Proteins; D004054:Diethylstilbestrol; D052244:Endocrine Disruptors; D000071221:Enhancer of Zeste Homolog 2 Protein; D004958:Estradiol; D004967:Estrogens; D009363:Neoplasm Proteins; D010636:Phenols; D063151:Polycomb Repressive Complex 2; D011960:Receptors, Estrogen; C452979:KMT2C protein, human; C120898:KMT2D protein, human; C498409:EZH2 protein, human; C578253:EZH2 protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: EZH2; endocrine disruptors; epigenetics; estrogen signaling; gene expression