title: Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis.
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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Not applicable.
authors.affiliation: Cixi Child and Maternal Hospital, 1288 Er'Zhaotan Road, Baishalu, Cixi, Zhejiang, China.
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ding
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China.|Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
authors.forename: Xishi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China. hoxa10@outlook.com.|Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China. hoxa10@outlook.com.
authors.forename: Sun-Wei
authors.initials: SW
authors.lastname: Guo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004715:Endometriosis / Q000188:drug therapy*; D005260:Female; D042421:Histone Code / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy*; D007150:Immunohistochemistry; D008745:Methylation; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D014191:Tranylcypromine / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D006657:Histones; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D056466:Histone Demethylases; C504076:KDM1a protein, mouse
keywords: Endometriosis; Epithelial-mesenchymal transition; Generalized hyperalgesia; Hotplate latency; Lysine-specific demethylase 1; Mouse; Tranylcypromine