Abstract
BackgroundGrowing 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.MethodsForty-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).ResultsTC 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.ConclusionIn 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 registrationNot applicable.
Highlights
Growing evidence indicates that endometriosis is an epigenetic disease
We have recently shown that lysine-specific demethylase 1 (LSD1) gene and protein expression is elevated in endometriosis, and treatment of endometriotic stromal cells with tranylcypromine (TC), an LSD1 inhibitor, significantly reduced cellular proliferation, cell cycle progression, and invasiveness [42]
We found that proliferating cell nuclear antigen (PCNA), mono-methylated lysine at histone H3 (H3K4me1) and di-methylated lysine at histone H3 (H3K4me2) staining was seen in cellular nuclei in both the stromal and epithelial cells of the ectopic endometrium, while vascular endothelial growth factor (VEGF)
Summary
Histone deacetylases (HDACs) and DNA methyltransferases have been shown to be promising targets by numerous in vitro studies. Endometriosis, characterized by the deposition and growth of functional endometrial-like tissues outside the uterine cavity, is an estrogen-dependent disease, affecting roughly 6–10 % of women of reproductive age [1]. Endometriosis is, first and foremost, a hormonal disease, characterized by the increased local production of estrogens due to molecular aberrations in steroidogenesis [5]. Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) have been shown to be promising targets by numerous in vitro studies [20,21,22,23,24]. Only a few studies have shown promising effects of HDAC inhibition in preclinical studies in endometriosis [25,26,27]
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