TET1 may contribute to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis.

ABSTRACT: Background:Endometriosis (EMs) is a non-malignant gynecological disease, whose pathogenesis remains to be clarified. Recent studies have found that hypoxia induces epithelial-mesenchymal transition (EMT) as well as epigenetic modification in EMs. However, the relationship between EMT and demethylation modification under hypoxia status in EMs remains unknown. Methods:The expression of N-cadherin, E-cadherin and TET1 in normal endometria, eutopic endometria and ovarian endometriomas was assessed by immunohistochemistry and immunofluorescence double staining. 5-hmC was detected by fluorescence-based ELISA kit using a specific 5-hmC antibody. Overexpression and inhibition of TET1 or hypoxia-inducible factor 2? (HIF-2?) were performed by plasmid and siRNA transfection. The expression of HIF-2?, TET1 and EMT markers in Ishikawa (ISK) cells (widely used as endometrial epithelial cells) was evaluated by western blotting. The interaction of HIF-2? and TET1 was analyzed by chromatin immunoprecipitation. Results:Demethylation enzyme TET1 (ten-eleven translocation1) was elevated in glandular epithelium of ovarian endometrioma, along with the activation of EMT (increased expression of N-cadherin, and decreased expression of E-cadherin) and global increase of epigenetic modification marker 5-hmC(5-hydroxymethylcytosine). Besides, endometriosis lesions had more TET1 and N-cadherin co-localized cells. Further study showed that ISK cells exhibited enhanced EMT, and increased expression of TET1 and HIF-2? under hypoxic condition. Hypoxia-induced EMT was partly regulated by TET1 and HIF-2?. HIF-2? inhibition mitigated TET1 expression changes provoked by hypoxia. Conclusions:Hypoxia induces the expression of TET1 regulated by HIF-2?, thus may promote EMT in endometriosis.

SUBMITTER: Wu J 

PROVIDER: S-EPMC7500323 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature