Estrogen degrades Scribble in endometrial epithelial cells through E3 ubiquitin ligase HECW1 in the development of diffuse adenomyosis

Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. In previous studies, the protein expression level of the polarity protein Scribble in the eutopic endometrium of patients with adenomyosis was found to be significantly decreased; however, little is known about its regulatory mechanism. 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 the expression of Scribble in vivo and in vitro. Firstly, we found Scribble was downregulated in eutopic endometrium and negatively related with aromatase P450 in tamoxifen-induced adenomyosis. Then, we established a 3D culture of primary endometrial epithelial cells and found that estrogen could disrupt apical-basal polarity of endometrial glandular epithelial cells. Based on the following experiments and GEO dataset screening, we found that estrogen regulates the expression level of Scribble by HECW1 through ubiquitination of Scribble protein. At last, we verified the expression of Scribble, HECW1, and aromatase P450 in eutopic endometrium of human and mouse specimens and found that the expression of HECW1 and aromatase P450 was significantly increased, while the expression of Scribble was significantly downregulated. Furthermore, a positive correlation was found between HECW1 and aromatase P450, while a negative correlation was found between HECW1 and Scribble in human clinical tissue specimens. Therefore, our research may provide a new understanding of the pathogenesis of adenomyosis. Summary Sentence In summary, estrogen induced disruption of apical-basal polarity in basal endometrial glandular epithelial cells through E3 ubiquitin ligase HECW1-mediated Scribble degradation might be one of the key mechanisms in the development of diffuse adenomyosis.