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

J Mol Biol. 2014 Oct 9;426(20):3426-41. doi: 10.1016/j.jmb.2014.07.025. Epub 2014 Aug 1.

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.

Keywords: EZH2; endocrine disruptors; epigenetics; estrogen signaling; gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diethylstilbestrol / pharmacology*
  • Endocrine Disruptors / pharmacology
  • Enhancer of Zeste Homolog 2 Protein
  • Estradiol / pharmacology*
  • Estrogens / pharmacology
  • Female
  • Gene Knockdown Techniques
  • Humans
  • MCF-7 Cells
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Ovariectomy
  • Phenols / pharmacology*
  • Polycomb Repressive Complex 2 / genetics*
  • Polycomb Repressive Complex 2 / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / metabolism
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic / drug effects*

Substances

  • Benzhydryl Compounds
  • DNA-Binding Proteins
  • Endocrine Disruptors
  • Estrogens
  • KMT2C protein, human
  • KMT2D protein, human
  • Neoplasm Proteins
  • Phenols
  • Receptors, Estrogen
  • Estradiol
  • Diethylstilbestrol
  • EZH2 protein, human
  • EZH2 protein, rat
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • bisphenol A