Endometriosis is an estrogen-dependent disease. Our previous study demonstrated that elevated levels of transcription factor 21 (TCF21) in endometriotic tissues enhanced steroidogenic factor-1 (SF-1) and estrogen receptor β (ERβ) expression by forming a heterodimer with upstream stimulatory factor 2 (USF2), allowing these TCF21/USF2 complexes to bind to the promoters of SF-1 and ERβ. Furthermore, TCF21 contributed to the increased proliferation of endometriotic stromal cells (ESCs), suggesting that TCF21 may play a vital role in the pathogenesis of endometriosis. SUMOylation is a posttranslational modification that has emerged as a crucial molecular regulatory mechanism. However, the mechanism regulating TCF21 SUMOylation in endometriosis is incompletely characterized. Thus, this study aimed to explore the effect of TCF21 SUMOylation on its expression and regulation in ovarian endometriosis. We found that the levels of SUMOylated TCF21 were increased in endometriotic tissues and stromal cells compared with eutopic endometrial tissues and stromal cells and enhanced by estrogen. Treatment with the SUMOylation inhibitor ginkgolic acid and the results of a protein half-life assay demonstrated that SUMOylation can stabilize the TCF21 protein. A coimmunoprecipitation assay showed that SUMOylation probably increased its interaction with USF2. Further analyses elucidated that SUMOylation of TCF21 significantly increased the binding activity of USF2 to the SF-1 and ERβ promoters. Moreover, the SUMOylation motifs in TCF21 affected the proliferation ability of ESCs. The results of this study suggest that SUMOylation plays a critical role in mediating the high expression of TCF21 in ESCs and may participate in the development of endometriosis.

Summary sentence

SUMOylation stabilized TCF21 and increased the binding activity of USF2 to the SF-1 and ERβ promoters by enhancing the formation of TCF21–USF2 complexes, thus promoting ESCs proliferation.