Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2016

Open Access 01-12-2016 | Research

Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis

Authors: Qunyan Sun, Ding Ding, Xishi Liu, Sun-Wei Guo

Published in: Reproductive Biology and Endocrinology | Issue 1/2016

Login to get access

Abstract

Background

Growing evidence indicates that endometriosis is an epigenetic disease. Encouragingly, histone deacetylases (HDACs) and DNA methyltransferases have been shown to be promising targets by numerous in vitro studies. However, only a few studies have shown promising effects of HDAC inhibition in preclinical studies in endometriosis. While lysine-specific demethylase 1 (LSD1) is recently found to be aberrantly expressed in endometriosis, and that the treatment of endometriotic stromal cells with tranylcypromine (TC), an LSD1 inhibitor, significantly reduced cellular proliferation, cell cycle progression, and invasiveness, the in vivo effect of TC treatment is currently lacking. This study sought to evaluate the effect of TC in a mouse model of endometriosis.

Methods

Forty-seven female C57BL/6 mice were used in this experimentation. All mice, except those randomly selected to form Sham surgery (M) and specificity control (S) groups, received an endometriosis-inducing surgery. Group S was set up mainly to ensure that the reduced generalized hyperalgesia in mice treated with TC is not due to any possible analgesic effect of TC, but rather resulting from the treatment effect specific to endometriosis. Two weeks after the surgery, mice that received surgery were further divided randomly into 3 groups: 1) untreated group (U); 2) low-dose TC group (L); 3) high-dose TC group (H). Group S received the same treatment as in group H. Two weeks after treatment, all mice were sacrificed and their ectopic endometrial tissues were harvested and analyzed by immunohistochemistry analysis. Hotplate test was administrated to all mice before the induction, treatment and sacrifice. Lesion size, hotplate latency, immunoreactivity against markers of proliferation, angiogenesis, H3K4 methylation, and of epithelial-mesenchymal transition (EMT).

Results

TC treatment significantly and substantially reduced the lesion size and improved generalized hyperalgesia in a dose-dependent fashion in mice with induced endometriosis. In addition, TC treatment resulted in reduced immunoreactivity to biomarkers of proliferation, angiogenesis, and H3K4 methylation, leading to arrested EMT and lesion growth.

Conclusion

In light of our previously reported reduced cellular proliferation, cell cycle progression and invasiveness resulting from the LSD1 inhibition in in vitro studies, our data strongly suggest that LSD1 is a promising therapeutic target for endometriosis.

Trial registration

Not applicable.
Literature
1.
2.
3.
Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco NF, de Cicco NC, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96:366–73. e8.CrossRefPubMedPubMedCentral
4.
Vercellini P, Crosignani P, Somigliana E, Vigano P, Frattaruolo MP, Fedele L. ‘Waiting for Godot’: a commonsense approach to the medical treatment of endometriosis. Hum Reprod. 2011;26:3–13.CrossRefPubMed
5.
Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005;57:359–83.CrossRefPubMed
6.
Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511–9.CrossRefPubMed
7.
Akoum A, Lemay A, Paradis I, Rheault N, Maheux R. Secretion of interleukin-6 by human endometriotic cells and regulation by proinflammatory cytokines and sex steroids. Hum Reprod. 1996;11:2269–75.CrossRefPubMed
8.
9.
Guo SW. Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large? Gynecol Obstet Invest. 2007;63:71–97.CrossRefPubMed
10.
Gonzalez-Ramos R, Donnez J, Defrere S, Leclercq I, Squifflet J, Lousse JC, et al. Nuclear factor-kappa B is constitutively activated in peritoneal endometriosis. Mol Hum Reprod. 2007;13:503–9.CrossRefPubMed
11.
Gonzalez-Ramos R, Van Langendonckt A, Defrere S, Lousse JC, Colette S, Devoto L, et al. Involvement of the nuclear factor-kappaB pathway in the pathogenesis of endometriosis. Fertil Steril. 2010;94:1985–94.CrossRefPubMed
12.
Nomiyama M, Hachisuga T, Sou H, Nakamura K, Matsumoto Y, Iwasaka T, et al. Local immune response in infertile patients with minimal endometriosis. Gynecol Obstet Invest. 1997;44:32–7.CrossRefPubMed
13.
Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Ishimaru T. Differential macrophage infiltration in early and advanced endometriosis and adjacent peritoneum. Fertil Steril. 2004;81:652–61.CrossRefPubMed
14.
Bacci M, Capobianco A, Monno A, Cottone L, Di Puppo F, Camisa B, et al. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. Am J Pathol. 2009;175:547–56.CrossRefPubMedPubMedCentral
15.
Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 2005;193:371–80.CrossRefPubMed
16.
17.
Colon-Diaz M, Baez-Vega P, Garcia M, Ruiz A, Monteiro JB, Fourquet J, et al. HDAC1 and HDAC2 are differentially expressed in endometriosis. Reprod Sci. 2012;19:483–92.CrossRefPubMedPubMedCentral
18.
Naqvi H, Ilagan Y, Krikun G, Taylor HS. Altered genome-wide methylation in endometriosis. Reprod Sci. 2014;21:1237–43.CrossRefPubMed
19.
Dyson MT, Kakinuma T, Pavone ME, Monsivais D, Navarro A, Malpani SS, et al. Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. Fertil Steril. 2015;104:953–63. e2.CrossRefPubMed
20.
Wu Y, Guo SW. Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780. Gynecol Obstet Invest. 2006;62:193–205.CrossRefPubMed
21.
Wu Y, Guo SW. Suppression of IL-1beta-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2007;135:88–93.CrossRefPubMed
22.
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;137:198–203.CrossRefPubMed
23.
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;94:2838–42.CrossRefPubMed
24.
Imesch P, Samartzis EP, Schneider M, Fink D, Fedier A. Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin. Fertil Steril. 2011;95:1579–83.CrossRefPubMed
25.
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;25:1014–25.CrossRefPubMed
26.
Zhao T, Liu X, Zhen X, Guo SW. Levo-tetrahydropalmatine retards the growth of ectopic endometrial implants and alleviates generalized hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. 2011;18:28–45.CrossRefPubMed
27.
Liu M, Liu X, Zhang Y, Guo SW. Valproic acid and progestin inhibit lesion growth and reduce hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. 2012;19:360–73.CrossRefPubMed
28.
Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, et al. New nomenclature for chromatin-modifying enzymes. Cell. 2007;131:633–6.CrossRefPubMed
29.
Cheng X, Blumenthal RM. Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. Biochemistry. 2010;49:2999–3008.CrossRefPubMedPubMedCentral
30.
Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119:941–53.CrossRefPubMed
31.
Mosammaparast N, Shi Y. Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem. 2010;79:155–79.CrossRefPubMed
32.
Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R, Karytinos A, et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc. 2010;132:6827–33.CrossRefPubMed
33.
Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet. 2009;41:125–9.CrossRefPubMed
34.
Perillo B, Ombra MN, Bertoni A, Cuozzo C, Sacchetti S, Sasso A, et al. DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science. 2008;319:202–6.CrossRefPubMed
35.
Lin T, Ponn A, Hu X, Law BK, Lu J. Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition. Oncogene. 2010;29:4896–904.CrossRefPubMedPubMedCentral
36.
Kashyap V, Ahmad S, Nilsson EM, Helczynski L, Kenna S, Persson JL, et al. The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer. Mol Oncol. 2013;7:555–66.CrossRefPubMedPubMedCentral
37.
Xiaomeng X, Ming Z, Jiezhi M, Xiaoling F. Aberrant histone acetylation and methylation levels in woman with endometriosis. Arch Gynecol Obstet. 2013;287:487–94.CrossRefPubMed
38.
Monteiro JB, Colon-Diaz M, Garcia M, Gutierrez S, Colon M, Seto E, et al. Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications. Reprod Sci. 2014;21:305–18.CrossRefPubMedPubMedCentral
39.
Samartzis EP, Noske A, Samartzis N, Fink D, Imesch P. The expression of histone deacetylase 1, but not other class I histone deacetylases, is significantly increased in endometriosis. Reprod Sci. 2013;20:1416–22.CrossRefPubMedPubMedCentral
40.
Banu SK, Lee J, Speights Jr VO, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. Mol Endocrinol. 2009;23:1291–305.CrossRefPubMed
41.
Arosh JA, Lee J, Starzinski-Powitz A, Banu SK. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 modulates DNA methylation and histone modification machinery proteins in human endometriotic cells. Mol Cell Endocrinol. 2015;409:51–8.CrossRefPubMed
42.
Ding D, Liu X, Guo SW. Overexpression of lysine-specific demethylase 1 in ovarian endometriomas and its inhibition reduces cellular proliferation, cell cycle progression, and invasiveness. Fertil Steril. 2014;101:740–9.CrossRefPubMed
43.
Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 2009;69:2065–71.CrossRefPubMed
44.
Jie Z, Li T, Jia-Yun H, Qiu J, Ping-Yao Z, Houyan S. Trans-2-phenylcyclopropylamine induces nerve cells apoptosis in zebrafish mediated by depression of LSD1 activity. Brain Res Bull. 2009;80:79–84.CrossRefPubMed
45.
Team. RC. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2013.
46.
Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Invasiveness of endometriotic cells in vitro. Lancet. 1995;346:1463–4.CrossRefPubMed
47.
Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Nonmalignant epithelial cells, potentially invasive in human endometriosis, lack the tumor suppressor molecule E-cadherin. Am J Pathol. 1997;150:461–7.PubMedPubMedCentral
48.
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;14:374–82.CrossRefPubMed
49.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMed
50.
Grund EM, Kagan D, Tran CA, Zeitvogel A, Starzinski-Powitz A, Nataraja S, et al. Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. Mol Pharmacol. 2008;73:1394–404.CrossRefPubMed
51.
Matsuzaki S, Darcha C. Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod. 2012;27:712–21.CrossRefPubMed
52.
Bartley J, Julicher A, Hotz B, Mechsner S, Hotz H. Epithelial to mesenchymal transition (EMT) seems to be regulated differently in endometriosis and the endometrium. Arch Gynecol Obstet. 2014;289:871–81.CrossRefPubMed
53.
Liao CJ, Li PT, Lee YC, Li SH, Chu ST. Lipocalin 2 induces the epithelial-mesenchymal transition in stressed endometrial epithelial cells: possible correlation with endometriosis development in a mouse model. Reproduction. 2014;147:179–87.CrossRefPubMed
54.
Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, et al. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 2010;29:1803–16.CrossRefPubMedPubMedCentral
55.
56.
McDonald OG, Wu H, Timp W, Doi A, Feinberg AP. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat Struct Mol Biol. 2011;18:867–74.CrossRefPubMedPubMedCentral
57.
Ferrari-Amorotti G, Fragliasso V, Esteki R, Prudente Z, Soliera AR, Cattelani S, et al. Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. Cancer Res. 2013;73:235–45.CrossRefPubMedPubMedCentral
58.
Chen LC, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, et al. Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study. J Affect Disord. 2016;190:282–5.CrossRefPubMed
59.
Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2014;28:2155–64.CrossRefPubMedPubMedCentral
60.
Vasilatos SN, Katz TA, Oesterreich S, Wan Y, Davidson NE, Huang Y. Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis. 2013;34:1196–207.CrossRefPubMedPubMedCentral
61.
Singh MM, Manton CA, Bhat KP, Tsai WW, Aldape K, Barton MC, et al. Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol. 2011;13:894–903.CrossRefPubMedPubMedCentral
62.
Huang PH, Chen CH, Chou CC, Sargeant AM, Kulp SK, Teng CM, et al. Histone deacetylase inhibitors stimulate histone H3 lysine 4 methylation in part via transcriptional repression of histone H3 lysine 4 demethylases. Mol Pharmacol. 2011;79:197–206.CrossRefPubMedPubMedCentral
63.
Zheng YC, Ma J, Wang Z, Li J, Jiang B, Zhou W, et al. A systematic review of histone lysine-specific demethylase 1 and its inhibitors. Med Res Rev. 2015;35:1032–71.CrossRefPubMed
Metadata
Title
Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis
Authors
Qunyan Sun
Ding Ding
Xishi Liu
Sun-Wei Guo
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2016
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-016-0154-0

Other articles of this Issue 1/2016

Reproductive Biology and Endocrinology 1/2016 Go to the issue

Research

Biallelic modification of IL2RG leads to severe combined immunodeficiency in pigs

Research

Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Research

Apolipoprotein B is regulated by gonadotropins and constitutes a predictive biomarker of IVF outcomes

Short communication

Experimental and bioinformatic analysis of cultured Bovine Endometrial Cells (BEND) responding to interferon tau (IFNT)

Research

The dynamics of trkA expression in the bovine ovary are associated with a luteotrophic effect of ovulation-inducing factor/nerve growth factor (OIF/NGF)

Research

Effects of cumulus cell removal time during in vitro fertilization on embryo quality and pregnancy outcomes: a prospective randomized sibling-oocyte study