Protein arginine methyltransferase (PRMT) plays essential roles in tumor initiation and progression, but its underlying mechanisms in the treatment sensitivity of endometrial cancer (EC) remain unclear and warrant further investigation. Here, a comprehensive analysis of the Cancer Genome Atlas database and Clinical Proteomic Tumor Analysis Consortium database identifies that PRMT3 plays an important role in EC. Specifically, further experiments show that PRMT3 inhibition enhances the susceptibility of EC cells to ferroptosis. Mechanistically, PRMT3 interacts with Methyltransferase 14 (METTL14) and is involved in its arginine methylation. In addition, PRMT3 inhibition‐mediated METTL14 overexpression promotes methylation modification via an m⁶A‐YTHDF2‐dependent mechanism, reducing Glutathione peroxidase 4 (GPX4) mRNA stability, increasing lipid peroxidation levels, and accelerating ferroptosis. Notably, combined PRMT3 blockade and anti‐PD‐1 therapy display more potent antitumor effects by accelerating ferroptosis in cell‐derived xenograft models. The specific PRMT3 inhibitor SGC707 exerts the same immunotherapeutic sensitizing effect in a patient‐derived xenograft model. Notably, blocking PRMT3 improves tumor suppression in response to cisplatin and radiation therapy. Altogether, this work demonstrates that PRMT3 depletion is a promising target for EC.

Background: Ovarian cancer is one of the important factors that seriously threaten women's health and its morbidity and mortality ranks eighth among female cancers in the world. It is critical to identify potential and promising biomarkers for prognostic evaluation and molecular therapy of OV. Ubiquitin-conjugating enzyme E2S (UBE2S), a potential oncogene, regulates the malignant progression of various tumors; however, its role in OV is still unclear. Methods: The expression and prognostic significance of UBE2S at the pan-cancer level were investigated through high-throughput gene expression analysis and clinical prognostic data from TCGA, GEPIA, and GEO databases. 181 patients with OV were included in this study. Cell culture and cell transfection were performed on OV cell lines (SKOV3 and A2780) and a normal ovarian cell line (IOSE80). The expression level and prognostic significance of UBE2S in OV were verified by western blot, immunohistochemistry, and Kaplan–Meier survival analysis. Through cell transfection, CCK-8, Ki-67 immunofluorescence, wound healing, Transwell, clonogenic, and flow cytometry assays, the effect and detailed mechanism of UBE2S knockdown on the malignant biological behavior of OV cells were explored. Results: UBE2S exhibited abnormally high expression at the pan-cancer level. The results of RT-qPCR and Western blotting indicated that UBE2S was significantly overexpressed in ovarian cancer cell lines compared with normal cell lines (P < 0.05). Kaplan–Meier survival analysis and Immunohistochemistry indicated that overexpression of UBE2S was related to poor prognosis of OV (HR > 1, P < 0.05). Results of in vitro experiments indicated that UBE2S gene knockdown might inhibit the proliferation, invasion, and prognosis of OV cells by inhibiting the PI3K/AKT/mTOR signaling pathway, thereby blocking the cell cycle and promoting apoptosis (P < 0.05). Conclusion: UBE2S is a potential oncogene strongly associated with a poor prognosis of OV patients. Knockdown of UBE2S could block the cell cycle and promote apoptosis by inhibiting the PI3K/AKT/mTOR pathway and ultimately inhibit the proliferation, migration and prognosis of ovarian cancer, which suggested that UBE2S might be used for molecular therapy and prognostic evaluation of ovarian cancer.

Background: Ubiquitin-binding enzyme E2T (UBE2T), a member of the E2 family of the ubiquitin–proteasome pathway, is associated with tumorigenesis of varioustumours; however, its role and mechanism in ovarian cancer remain unclear. Results: Our study revealed that UBE2T is highly expressed in ovarian cancer; this high expression was closely related to poor prognosis. Immunohistochemistry was used to validate the high expression of UBE2T in ovarian cancer. This is the first study to demonstrate that UBE2T expression is higher in ovarian cancer with BRCA mutation. Moreover, we demonstrated that UBE2T gene silencing significantly inhibited ovarian cancer cell proliferation and invasion. The epithelial–mesenchymal transition (EMT) of ovarian cancer cells and phosphatidylinositol 3 kinase/protein kinase B (PI3K-AKT) pathway were significantly inhibited. Adding the mechanistic target of rapamycin activator MHY1485 activated the PI3K-AKT pathway and significantly restored the proliferative and invasive ability of ovarian cancer cells. Furthermore, a tumorigenesis experiment in nude mice revealed that tumour growth on mice body surface and tumour tissue EMT were significantly inhibited after UBE2T gene silencing. Conclusions: This study demonstrated that UBE2T regulates EMT via the PI3K-AKT pathway and plays a carcinogenic role in ovarian cancer. Moreover, UBE2T may interact with BRCA to affect ovarian cancer occurrence and development. Hence, UBE2T may be a valuable novel biomarker for the early diagnosis and prognosis and treatment of ovarian cancer. Further, UBE2T inhibition may be effective for treating ovarian cancer.

Background: Exploring novel and sensitive targets is urgent due to the high morbidity of endometrial cancer (EC). The purpose of our study was to explore the transcription factors and immune-related genes in EC and further identify immune-based lncRNA signature as biomarker for predicting survival prognosis.Methods: Transcription factors, aberrantly expressed immune-related genes and immune-related lncRNAs were explored through bioinformatics analysis. Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis were conducted to identify the immune and overall survival (OS) related lncRNAs. The accuracy of model was evaluated by Kaplan–Meier method and receiver operating characteristic (ROC) analysis, and the independent prognostic indicator was identified with Cox analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) were conducted to detect the accuracy of our results.Results: A network of 29 transcription factors and 17 immune-related genes was constructed. Furthermore, four immune-prognosis-related lncRNAs were screened out. Kaplan–Meier survival analysis and time-dependent ROC analysis revealed a satisfactory predictive potential of the 4-lncRNA model. Consistency was achieved among the results from the training set, testing set and entire cohort. The distributed patterns between the high- and low-risk groups could be distinguished in principal component analysis. Comparisons of the risk score and clinical factors confirmed the four-lncRNA-based signature as an independent prognostic indicator. Last, the reliability of the results was verified by qRT-PCR in 29 cases of endometrial carcinoma and in cells.Conclusions: Overall, our study constructed a network of transcription factors and immune-related genes and explored a four immune-related lncRNA signature that could serve as a novel potential biomarker of EC.

Background. Endometrial cancer is one of the three major gynecologic malignancies, and its incidence continues to rise. ATPase family AAA structural domain-containing protein 2 (ATAD2) is an ATPase protein, which is an independent factor for poor prognosis in endometrial cancer. However, its role in the disease is yet to be determined. Methods. The Tumor IMmune Estimation Resource (TIMER) database was used to assess ATAD2 expression in pan-cancer, and the relevance of ATAD2 expression in Uterine Corpus Endometrial Carcinoma (UCEC) in clinical settings was obtained using Gene Expression Profiling Interactive Analysis (GEPIA) and UALCAN analysis. In addition, the Human Protein Atlas database was used to assess ATAD2 protein expression in UCEC. Furthermore, in vitro molecular biology and in vivo functional experiments were employed to ascertain the effect of ATAD2 expression on tumor angiogenesis and tumor growth. UALCAN was used to screen for ATAD2 coexpressed genes, and Sangerbox was utilized to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of these coexpressed genes. Finally, the TIMER, Tumor Immune System Interaction and Drug Bank (TISIDB), and GEPIA databases were used to analyze the relationship between ATAD2 and immune infiltration. Results. ATAD2 is highly expressed in a variety of tumors, and in UCEC, it plays the role of a protooncogene. Basic experiments revealed that ATAD2 promotes vascular endothelial growth factor expression in endometrial cancer and affects tumor growth and angiogenesis. In addition, GO and KEGG enrichment analyses showed that ATAD2-associated genes were chiefly enriched in certain signaling pathways, such as herpes simplex virus 1 infection and that ATAD2 was associated with immune infiltration in UCEC. Conclusion. Our findings suggest that ATAD2 promotes tumor growth and angiogenesis in endometrial cancer. Furthermore, ATAD2 is associated with immune infiltration and is a potential diagnostic and therapeutic target.