Estrogen Regulates Scribble Localization in Endometrial Epithelial Cells Through Acyl Protein Thioesterase (APT)-Mediated S-Palmitoylation in Adenomyosis

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 Similar content being viewed by others Data Availability The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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We are grateful to the women who participated in this study and Shanghai Key Laboratory of Female Reproductive Endocrine Related Disease, Fudan University (Shanghai, China), for providing experimental platform. Graphical abstract was created with BioRender.com. Code Availability Not applicable. Funding This work was supported by funding from the National Natural Science Foundation of China (No. 82001523) and Gusu Health Talent Project (No. GSWS2021004). Author information Authors and Affiliations Contributions Z. J. performed the lab experiments and wrote the manuscript. J. W. designed the study and edited the manuscript. Y. C. supervised the research project and gave final approval. All authors reviewed the manuscript. Corresponding authors Ethics declarations Ethics Approval Appropriate ethical approvals were obtained for the study. Consent to Participate Informed consent was obtained from the study participants. Consent for Publication This manuscript has not been published or presented elsewhere and is not under consideration by another journal. All study participants provided informed consent and approved it for publication. Conflict of Interest The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Jin, Z., Wang, J. & Chen, Y. Estrogen Regulates Scribble Localization in Endometrial Epithelial Cells Through Acyl Protein Thioesterase (APT)-Mediated S-Palmitoylation in Adenomyosis. Reprod. Sci. 31, 128–138 (2024). https://doi.org/10.1007/s43032-023-01319-4 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-023-01319-4