Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
Biol Reprod. 2021 Jul 2;105(1):128-136. doi: 10.1093/biolre/ioab038.
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.
子宫内膜异位症是一种雌激素依赖性疾病。我们之前的研究表明，子宫内膜异位症组织中转录因子 21（TCF21）水平升高，通过与上游刺激因子 2（USF2）形成异二聚体，增强类固醇生成因子 1（SF-1）和雌激素受体β（ERβ）的表达，使这些 TCF21/USF2 复合物能够结合到 SF-1 和 ERβ 的启动子上。此外，TCF21 促进了子宫内膜异位症基质细胞（ESCs）的增殖，提示 TCF21 可能在子宫内膜异位症的发病机制中发挥重要作用。SUMOylation 是一种翻译后修饰，已成为一种重要的分子调节机制。然而，子宫内膜异位症中 TCF21 SUMOylation 的调节机制尚不完全清楚。因此，本研究旨在探讨 TCF21 SUMOylation 对卵巢子宫内膜异位症中其表达和调控的影响。我们发现，与在位子宫内膜组织和基质细胞相比，子宫内膜异位症组织和基质细胞中 SUMOylated TCF21 的水平升高，并受雌激素增强。SUMOylation 抑制剂白果内酯处理和蛋白半衰期测定结果表明，SUMOylation 可以稳定 TCF21 蛋白。免疫共沉淀实验表明，SUMOylation 可能增加了它与 USF2 的相互作用。进一步分析表明，TCF21 的 SUMOylation 显著增加了 USF2 与 SF-1 和 ERβ 启动子的结合活性。此外，TCF21 中的 SUMOylation 基序影响 ESCs 的增殖能力。本研究结果表明，SUMOylation 在介导 ESCs 中 TCF21 的高表达中起关键作用，可能参与子宫内膜异位症的发生。
