Xing Zhou

UBE2C -mediated Autophagy Inhibition via Ubiquitination of SIRT1 Contributes to Endometrial Cancer Progression

Abstract Recent studies have shown that autophagy plays an important role in gynecologic tumors, and ubiquitin modification of autophagy regulatory components is essential to regulate autophagic flux. In this study, we found that the ubiquitin-conjugating enzyme E2C (UBE2C) affects endometrial cancer cell apoptosis and proliferation by inhibiting autophagy. Electron microscopy observation of cell ultrastructure and experimental biochemical analysis showed that endometrial cancer cells with UBE2C expression knocked down display typical autophagic characteristics. Cells were cotreated with the autophagy pharmacologic inhibitors chloroquine and/or bafilomycin A1, and mRFP-GFP-LC3 assays were performed to monitor autophagic flux and determine whether UBE2C suppresses the autophagy program. Investigation of the corresponding mechanism by which UBE2C inhibits autophagy revealed that UBE2C induces K48-linked SIRT1 ubiquitination and promotes ubiquitination-dependent degradation of SIRT1, subsequently reducing H4K16 deacetylation levels and epigenetically inhibiting the expression of autophagy-related genes. The results of cell counting kit-8, Hoechst staining, and immunofluorescence assays further indicated that deletion of the autophagy-related gene BECN1 significantly attenuates UBE2C knockdown–induced cell apoptosis. Moreover, overexpression of UBE2C promoted tumor growth in the xenograft mice model. While, the introduction of rapamycin, an agonist of autophagy, successfully reversed tumor growth and apoptosis inhibition mediated by UBE2C overexpression in vitro and in vivo. Taken together, our results suggested that UBE2C-mediated ubiquitination and degradation of SIRT1 contribute to the malignant progression of endometrial cancer through epigenetic inhibition of autophagy. Implications: Our study highlights the tumorigenic role and regulatory mechanism of UBE2C in endometrial cancer; UBE2C inhibits endometrial cancer cell apoptosis through autophagy-related mechanisms and our findings provide new insights into the treatment of endometrial cancer.

Analysis of carcinogenic signaling networks in endometrial cancer identifies RAB17 as a potential target

AbstractEndometrial cancer is one of the most common malignancies in postmenopausal women. Several potential therapeutic targets have been investigated in current research, but few have been used clinically. Therefore, further investigating the potential pathogenesis of endometrial cancer and new effective therapeutic targets for endometrial malignancies is still necessary. Our study used a The Cancer Genome Atlas dataset and two Gene Expression Omnibus datasets for weighted gene coexpression network analysis to identify important genes associated with the histological grades of endometrial cancer. In addition, we performed gene set enrichment analysis on the three datasets and found that abnormally activated signaling pathways and metabolic pathways are the main biological behaviors of endometrial cancer. Moreover, we further used different algorithms and identified the RAB17 gene as a potential study object. To further illustrate the potential role of the genes we analyzed in clinical and cellular aspects, we performed a clinical correlation analysis. Finally, we demonstrated the important roles and mechanisms of the RAB17 gene in the cell cycle, proliferation, and metastasis of endometrial cancer. Using repeated database analysis and cell‐level assays, we propose RAB17 as a potential target gene for endometrial cancer for further study.