title: Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo.
abstract: Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES-induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States.
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, United States.
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, United States.
authors.forename: Khairul I
authors.initials: KI
authors.lastname: Ansari
authors.affiliation: Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, United States.
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, United States.
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, United States. Electronic address: smandal@uta.edu.
authors.forename: Subhrangsu S
authors.initials: SS
authors.lastname: Mandal
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D001559:Benzhydryl Compounds / Q000633:toxicity*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D020218:Response Elements; D015533:Transcriptional Activation / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004054:Diethylstilbestrol; D052244:Endocrine Disruptors; D004958:Estradiol; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D051788:Myeloid-Lymphoid Leukemia Protein; D010636:Phenols; D062085:RNA, Long Noncoding; D011960:Receptors, Estrogen; C561566:HOTAIR long untranslated RNA, human; C497422:KMT2A protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol A; Diethylstilbestrol; Endocrine disruption; Epigenetics; HOTAIR; LncRNA; Transcriptional regulation