Estrogen Regulates Scribble Localization in Endometrial Epithelial Cells Through Acyl Protein Thioesterase (APT)-Mediated S-Palmitoylation in Adenomyosis.
Estrogen Regulates Scribble Localization in Endometrial Epithelial Cells Through Acyl Protein Thioesterase (APT)-Mediated S-Palmitoylation in Adenomyosis.
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DOI：
10.1007/s43032-023-01319-4
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发表时间：
2023-08
影响因子：
2.9
通讯作者：
Zhixing Jin;Juan Wang;Youguo Chen
中科院分区：
文献类型：
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作者：
Zhixing Jin;Juan Wang;Youguo Chen
尽管其发病率和症状的严重性，对子宫腺肌病的发病机制和病因知之甚少。在我们之前的研究中，已经发现Scribble定位部分移位到细胞质；然而，其调控机制是已知的。鉴于子宫内膜超生理性雌激素的产生在子宫腺肌病发生发展中的重要作用，我们在体内和体外分析了雌激素对Scribble定位的影响和机制。首先，我们发现在子宫腺肌病患者和子宫腺肌病患者中，Scribble从基底膜到细胞质的移位很容易出现(分别为68%比27%，60%比10%)。用S棕榈酰化抑制剂2-溴-棕榈酸酯处理48h后，免疫荧光、Western印迹和酰基生物素交换棕榈酰化实验观察到胞浆内Scribble蛋白的丰富和Palm-Scribble蛋白的减少。高雌激素暴露不仅可诱导Scribble细胞部分胞浆易位，还可降低Palm-Scribble基因的表达水平，这种作用可被雌激素受体抑制剂ICI182,780所恢复。在后续实验的基础上，我们发现雌激素通过S棕榈酰化Scribble蛋白来调节APT对Scribble定位的调控。最后，应用免疫组织化学方法检测APT1和APT2在人临床组织中的表达，发现APT1和APT2的表达均显著增加。此外，APT1或APT2与芳香酶P450呈正相关。因此，我们的研究可能会对子宫腺肌症的发病机制提供新的认识。
Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. In our previous study, Scribble localization has been found to be partially translocated to cytoplasm; however, its regulatory mechanism is known. In consideration of the important role of supraphysiologic estrogen production in the endometrium in the development of adenomyosis, we analyzed the effect and mechanism of estrogen on Scribble localization in vivo and in vitro. Firstly, we found Scribble translocation from the basolateral membrane to the cytoplasm was easily to be seen in women and mice with adenomyosis (68% vs 27%, 60% vs 10% separately). After treatment with the S-palmitoylation inhibitor 2-bromopalmitate for 48H, cytoplasmic enrichment of Scribble and the reduced level of palm-Scribble was observed by immunofluorescence, Western blot, and acyl-biotin exchange palmitoylation assay. High estrogen exposure could not only induce partially cytoplasmic translocation of Scribble but also decrease the expression level of palm-Scribble, which can be recovered by estrogen receptor inhibitor ICI182,780. Based on following experiments, we found that estrogen regulated Scribble localization by APT through S-palmitoylation of Scribble protein. At last, IHC was performed to verify the expression of APT1 and APT2 in human clinical tissue specimens and found that they were all increased dramatically. Furthermore, positive correlations were found between APT1 or APT2 and aromatase P450. Therefore, our research may provide a new understanding of the pathogenesis of adenomyosis.Graphical Abstract