Abstract
Epigenetic mechanisms have been ascribed important roles in endometriosis. Covalent histone modifications at lysine residues have been shown to regulate gene expression and thus contribute to pathological states in many diseases. In endometriosis, histone deacetylase inhibition (HDACi) resulted in reactivation of E-cadherin, attenuation of invasion, decreased proliferation of endometriotic cells, and caused lesion regression in an animal model. This study was conducted to assess basal and hormone-regulated gene expression levels of HDAC1 and HDAC2 (HDAC1/2) in cell lines and protein expression levels in tissues. Basal and steroid hormone-regulated HDAC1/2 gene expression levels were determined by quantitative polymerase chain reaction in cell lines and tissues. Protein levels were measured by immunohistochemistry (IHC) in tissues on an endometriosis tissue micro-array (TMA). Basal HDAC1/2 gene expression levels were significantly higher in endometriotic versus endometrial stromal cells, which was confirmed by Western blot analysis. Estradiol (E2) and progesterone (P4) significantly downregulated HDAC1 expression in endometrial epithelial cells. Levels of HDAC2 were upregulated by E2 and downregulated by E2 + P4 in endometrial stro-mal cells. Hormone modulation of HDAC1/2 gene expression was lost in the endometriotic cell line. Immunohistochemistry showed that HDAC1/2 proteins were expressed in a substantial proportion of lesions and endometrium from patients, and their expression levels varied according to lesion localization. The highest proportion of strong HDAC1 immunostaining was seen in ovarian, skin, and gastrointestinal lesions, and of HDAC2 in skin lesions and endometrium from patients with endometriosis. These studies suggest that endometriosis etiology may be partially explained by epigenetic regulation of gene expression due to dysregulations in the expression of HDACs.
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References
Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.
Flores I, Rivera E, Ruiz LA, Santiago OI, Vernon MW, Appleyard CB. Molecular profiling of experimental endometriosis identified gene expression patterns in common with human disease. Fertil Steril. 2007;87(5):1180–1199.
Konno R, Fujiwara H, Netsu S, et al. Gene expression profiling of the rat endometriosis model. Am J Reprod Immunol. 2007;58(4):330–343.
Eyster KM, Boles AL, Brannian JD, Hansen KA. DNA microarray analysis of gene expression markers of endometriosis. Fertil Steril. 2002;77(1):38–42.
Matsuzaki S, Canis M, Pouly JL, Botchorishvili R, Dechelotte PJ, Mage G. Differential expression of genes in eutopic and ectopic endometrium from patients with ovarian endometriosis. Fertil Steril. 2006;86(3):548–553.
Kao LC, Germeyer A, Tulac S, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144(7):2870–2881.
Guo SW. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15(10):587–607.
Shabason JE, Tofilon PJ, Camphausen K. HDAC inhibitors in cancer care. Oncology (Williston Park). 2010;24(2):180–185.
Marks PA. HDAC inhibitors: much to learn about effective therapy. Oncology (Williston Park). 2010;24(2):185, 188.
Sleiman SF, Basso M, Mahishi L, et al. Putting the ‘HAT’ back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions. Expert Opin Investig Drugs. 2009;18(5):573–584.
Bertrand P. Inside HDAC with HDAC inhibitors. Eur J Med Chem. 2010;45(6):2095–2116.
Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol. 2000;184(1):1–16.
Wu Y, Starzinski-Powitz A, Guo SW. Trichostatin A, a histone deacetylase inhibitor, attenuates invasiveness and reactivates E-cadherin expression in immortalized endometriotic cells. Reprod Sci. 2007;14(4):374–382.
Wu Y, Starzinski-Powitz A, Guo SW. Capsaicin inhibits proliferation of endometriotic cells in vitro. Gynecol Obstet Invest. 2008;66(1):59–62.
Wu Y, Guo SW. Histone deacetylase inhibitors trichostatin A and valproic acid induce cell cycle arrest and p21 expression in immortalized human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2008;137(2):198–203.
Imesch P, Fink D, Fedier A. Romidepsin reduces histone deacetylase activity, induces acetylation of histones, inhibits proliferation, and activates apoptosis in immortalized epithelial endometriotic cells. Fertil Steril. 2010;94(7):2838–2842.
Lu Y, Nie J, Liu X, Zheng Y, Guo SW. Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Hum Reprod. 2010;25(4):1014–1025.
Bulun SE, Cheng YH, Pavone ME, et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):36–43.
Cunliffe VT. Eloquent silence: developmental functions of Class I histone deacetylases. Curr Opin Genet Dev. 2008;18(5):404–410.
Hombach-Klonisch S, Kehlen A, Fowler PA, et al. Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells. J Mol Endocrinol. 2005;34(2):517–534.
Krikun G, Mor G, Alvero A, et al. A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology. 2004;145(5):2291–2296.
Ruiz A, Salvo VA, Ruiz LA, Baez P, Garcia M, Flores I. Basal and steroid hormone-regulated expression of CXCR4 in human endometrium and endometriosis. Reprod Sci. 2010;17(10):894–903.
Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402–408.
Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263.
Sakai N, Maruyama T, Sakurai R, et al. Involvement of histone acetylation in ovarian steroid-induced decidualization of human endometrial stromal cells. J Biol Chem. 2003;278(19):16675–16682.
Uchida H, Maruyama T, Nagashima T, Asada H, Yoshimura Y. Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin. Endocrinology. 2005;146(12):5365–5373.
Bulun SE, Cheng YH, Pavone ME, et al. 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):44–50.
Luo Y, Jian W, Stavreva D, et al. Trans-regulation of histone deacetylase activities through acetylation. J Biol Chem. 2009; 284(50):34901–34910.
Dannenberg JH, David G, Zhong S, van der Torre J, Wong WH, Depinho RA. mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival. Genes Dev. 2005;19(13):1581–1595.
Peinado H, Ballestar E, Esteller M, Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2004; 24(1):306–319.
Grzenda A, Lomberk G, Zhang JS, Urrutia R. Sin3: master scaffold and transcriptional corepressor. Biochim Biophys Acta. 2009; 1789(6–8):443–450.
Hayashi A, Horiuchi A, Kikuchi N, et al. Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin. Int J Cancer. 2010;127(6):1332–1346.
Wilting RH, Yanover E, Heideman MR, et al. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haemato-poiesis. EMBO J. 2010;29(15):2586–2597.
Yamaguchi T, Cubizolles F, Zhang Y, et al. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev. 2010;24(5):455–469.
Krusche CA, Vloet AJ, Classen-Linke I, von Rango U, Beier HM, Alfer J. Class I histone deacetylase expression in the human cyclic endometrium and endometrial adenocarcinomas. Hum Reprod. 2007;22(11):2956–2966.
Munro SK, Farquhar CM, Mitchell MD, Ponnampalam AP. Epigenetic regulation of endometrium during the menstrual cycle. Mol Hum Reprod. 2010;16(5):297–310.
Nisolle M. Ovarian endometriosis and peritoneal endometriosis: are they different entities from a fertility perspective? Curr Opin Obstet Gynecol. 2002;14(3):283–288.
Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68(4):585–596.
Weichert W. HDAC expression and clinical prognosis in human malignancies. Cancer Lett. 2009;280(2):168–176.
Fakhry H, Miyamoto T, Kashima H, et al. Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells. Hum Pathol. 2010;41(6):848–858.
Weichert W, Denkert C, Noske A, et al. Expression of class I histone deacetylases indicates poor prognosis in endometrioid subtypes of ovarian and endometrial carcinomas. Neoplasia. 2008;10(9):1021–1027.
Weichert W, Roske A, Niesporek S, et al. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res. 2008;14(6):1669–1677.
Nezhat F, Datta MS, Hanson V, Pejovic T, Nezhat C. The relationship of endometriosis and ovarian malignancy: a review. Fertil Steril. 2008;90(5):1559–1570.
Ness RB. Endometriosis and ovarian cancer: thoughts on shared pathophysiology. Am J Obstet Gynecol. 2003;189(1):280–294.
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Colón-Díaz, M., Báez-Vega, P., García, M. et al. HDAC1 and HDAC2 are Differentially Expressed in Endometriosis. Reprod. Sci. 19, 483–492 (2012). https://doi.org/10.1177/1933719111432870
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DOI: https://doi.org/10.1177/1933719111432870