title: Selective inhibition of prostaglandin E2 receptors EP2 and EP4 modulates DNA methylation and histone modification machinery proteins in human endometriotic cells.
abstract: Endometriosis is an inflammatory gynecological disease of reproductive-age women. The prevalence of endometriosis is 5-10% in reproductive-age women. Modern medical treatments are directed to inhibit the action of estrogen in endometriotic cells. However, hormonal therapies targeting estrogen can be prescribed only for a short time because of their undesirable side effects. Recent studies from our laboratory, using human endometriotic epithelial cell line 12Z and stromal cell line 22B derived from red lesion, discovered that selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits adhesion, invasion, growth, and survival of 12Z and 22B cells by modulating integrins, MMPs and TIMPs, cell cycle, survival, and intrinsic apoptotic pathways, suggesting multiple epigenetic mechanisms. The novel findings of the present study indicate that selective pharmacological inhibition of EP2 and EP4: (i) decreases expression of DNMT3a, DNMT3b, H3K9me3, H3K27me3, SUV39H1, HP1a, H3K27, EZH2, JMJD2a, HDAC1, HDAC3, MeCP2, CoREST and Sin3A; (ii) increases expression of H3K4me3, H3H9ac, H3K27ac; and (iii) does not modulate the expression of DNMT1, hSET1, LSD1, MBD1, p300, HDAC2, and JMJD3 epigenetic machinery proteins in an epithelial and stromal cell specific manner. In this study, we report for the first time that inhibition of PGE2-EP2/EP4 signaling modulates DNA methylation, H3 histone methylation and acetylation, and epigenetic memory machinery proteins in human endometriotic epithelial cells and stromal cells. Thus, targeting EP2 and EP4 receptors may emerge as long-term nonsteroidal therapy for treatment of active endometriotic lesions in women.
authors.affiliation: Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, 77843 Texas, USA. Electronic address: jarosh@cvm.tamu.edu.
authors.forename: Joe A
authors.initials: JA
authors.lastname: Arosh
authors.affiliation: Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, 77843 Texas, USA.
authors.forename: JeHoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Molekulare Zellbiologie und Humangenetik, Institut für Zellbiologie und Neurowissenschaft, Siesmayerstraße 70, Geb. B, 60323 Frankfurt am Main, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Starzinski-Powitz
authors.affiliation: Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, 77843 Texas, USA.
authors.forename: Sakhila K
authors.initials: SK
authors.lastname: Banu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002460:Cell Line; D019175:DNA Methylation / Q000187:drug effects*; D004715:Endometriosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D006657:Histones; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D011448:Prostaglandin Antagonists; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; C046926:AH 23848
keywords: DNA methylation; EP2 and EP4; Endometriosis; Epigenetics; Histone modification; PGE(2)
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