Introduction: It is a member of polycomb group of proteins. EZH2, a histone 3 lysine 27 specific methyltransferase, acts as a gene silencer and is also overexpressed in prostate and breast carcinomas. It is a component of polycomb repressive complex 2 (PRC2). PRC2 is involved in transient gene silencing by causing H3K27 tri-methyl marks in the promoter regions of various genes. Overexpression of EZH2 leads to augmented tumorigenesis in mice and oncogenic phenotype, while knockdown via RNAi leads to decreased cell proliferation, cellular invasiveness and metastasis. In this study, we investigated the mechanism of transcriptional regulation of EZH2 by estradiol and other estrogenic endocrine disrupting chemicals, BPA and DES. Methods: MCF7 (human adenocarcinoma mammary, ER-positive) cells were treated with estradiol, bisphenol-A (BPA) and diehtylstilbesterol (DES), RNA and protein were analyzed by qPCR and western blot, respectively. ChIP analyses on estradiol/BPA/DES treated and control cells were performed with appropriate antibodies.Results: Our studies demonstrated that EZH2 is transcriptionally up regulated by estradiol, BPA and DES both in vitro and in vivo. EZH2 promoter contains functional estrogen-response elements (EREs), identified via luciferase assay. Estrogen-receptors (ERa and ER�) and ER-coregulators such as MLL-histone methylases (MLL2 and MLL3) bind to the promoter of EZH2 in the presence of estradiol, BPA and DES. Thus aiding in estradiol, BPA and DES mediated up regulation of EZH2, in vitro.Conclusion: EZH2 is transcriptionally regulated by estradiol and EDCs such as BPA and DES via recruitment of ERa and ER� to the functional EREs along with ER-coregulators such as MLL2 and MLL3 and modify the chromatin, leading to the recruitment of RNA polymerase II to the promoter region of EZH2. Thus, up regulating the expression of EZH2

Mechanism of transcriptional regulation of EZH2 (H3K27 methyltranferase) by 17�-estradiol  and estrogenic endocrine disrupting chemicals

247th National Meeting (2014)

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