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

Abstract

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 down-regulated 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 used found that estrogen could disrupt apical-basal polarity of endometrial glandular epithelial cells. Based on the following experiments and GEO datasets screening, we found 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 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.

Animal Models of Adenomyosis

“…Subfertility 50 MMP inhibitors, 45,90 danazol, [72][73][74] GnRH antagonist, 73 SPRMs, [78][79][80] fulvestrant, 73 rhein, 87 angiogenesis inhibitor, 91 probucol 92 Tamoxifen treatment Increased NGF, 36,59,62,63 decreased scribble, 66 increased collagens, 62 platelet-induced EMT 65 Hyperalgesia, [82][83][84][85][86]88,93 subfertility 76,100 GnRH agonist, 76 l-THP, 82 andrographolide, 82 EGCG, 83,84 resveratrol, 85 leonurine, 86 VPA, 82,86,88 antiplatelet therapy 93 β-Catenin activation E2-induced EMT 26 Infertility 99 N/A Xenotransplantation E2/VEGF-induced angiogenesis, 38 E2-induced EMT 40,41 N/A ANXA2 inhibitor, 41 raloxifene, …”

“…62,65 A mechanism for E2-induced loss of epithelial cell polarity has also been proposed based on data showing a decrease of the polarity-related protein scribble in tamoxifen-induced murine adenomyosis. 66 EMT is also associated with increased collagen production leading to fibrosis, and collagens have been found to be upregulated in murine adenomyosis tissue. 62 Moreover, support for the importance of E2-induced EMT in adenomyotic lesion growth has been validated by data from mice with human adenomyosis xenotransplants.…”

Integrating Network Pharmacology and Experimental Validation Deciphers the Mechanism of Guizhi Fuling Wan against Adenomyosis

“…It has been reported that AM is usually accompanied by a high level of estrogen [ 17 ], and the critical enzyme expression of estrogen metabolism regulation in ectopic endometrial stromal cells is significantly increased [ 18 ]. Targeting estrogen has excellent potential in the therapy of AM [ 19 , 20 ]. In our study, 9 out of 55 compounds from GZFLW may act as estrogen regulators, including beta-sitosterol, hederagenin, quercetin, paeoniflorin, kaempferol, taxifolin, pachymic acid, ellagic acid, and baicalein.…”

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

“…Functional studies on these two proteins are just beginning. NEDL1 is involved in the Wnt signaling pathway by ubiquitination and degradation of Dishevelled-1 (Dvl1) [ 5 , 52 , 53 ]. Recent findings support that NEDL1 is also implicated in the TGF-β signaling pathway by ubiquitination of Smad4 [ 54 ].…”