title: Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis.
abstract: Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A-exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis.
authors.affiliation: Science Park Research Division, Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
authors.forename: K Leigh
authors.initials: KL
authors.lastname: Greathouse
authors.forename: Tiffany
authors.initials: T
authors.lastname: Bredfeldt
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Everitt
authors.forename: Kevin
authors.initials: K
authors.lastname: Lin
authors.forename: Tia
authors.initials: T
authors.lastname: Berry
authors.forename: Kurunthachalam
authors.initials: K
authors.lastname: Kannan
authors.forename: Megan L
authors.initials: ML
authors.lastname: Mittelstadt
authors.forename: Shuk-mei
authors.initials: SM
authors.lastname: Ho
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D004967:Estrogens / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D063151:Polycomb Repressive Complex 2; D051381:Rats; D012307:Risk Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D004967:Estrogens; D014157:Transcription Factors; D019833:Genistein; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2