UBE2T regulates epithelial–mesenchymal transition through the PI3K-AKT pathway and plays a carcinogenic role in ovarian cancer

Cui, Ping; Li, Hao; Wang, Can; Liu, Yuan; Zhang, Mengjun; Yin, Yue; Sun, Zhenxing; Wang, Yiru; Chen, Xiuwei

doi:10.1186/s13048-022-01034-9

Cited by 7 publications

(2 citation statements)

References 57 publications

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“…It is critical for the initiation and progression of pancreatic cancer (Zheng et al, 2020) and has been demonstrated to promote the proliferation of renal cell carcinoma cells through regulating phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signaling (Hao et al, 2019). Suppression of UBE2T activity has also exhibited an inhibitory effect on the proliferation and invasion of ovarian cancer cells (Cui et al, 2022), lung adenocarcinoma (Li et al, 2022), and other cancers (Liu et al, 2017). Finally, UBE2T also plays important roles in primary cellular processes and participates in protein–protein interactions (Hodson et al, 2014; Lim et al, 2016; Longerich et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

Loh,

Anantharajan,

Huang

et al. 2024

Protein Science

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UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin‐conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug‐like small molecules. Here, we performed fragment screening using 19F‐nuclear magnetic resonance (NMR) and validated the hits with 1H‐15N‐heteronuclear single quantum coherence (HSQC) experiment and X‐ray crystallographic studies. The cocrystal structures obtained revealed the binding modes of the hit fragments and allowed for the characterization of the fragment‐binding sites. Further screening of structural analogues resulted in the identification of a compound series with inhibitory effect on UBE2T activity. Our current study has identified two new binding pockets in UBE2T, which will be useful for the development of small molecules to regulate the function of this protein. In addition, the compounds identified in this study can serve as chemical starting points for the development of UBE2T modulators.

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Section: Introductionmentioning

confidence: 99%

Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

Loh,

Anantharajan,

Huang

et al. 2024

Protein Science

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“… 10–14 UBE2T facilitates the occurrence and development of ovarian cancer by regulating epithelial–mesenchymal transition (EMT) through the PI3K-AKT pathway. 15 Further, silencing of UBE2T represses lung adenocarcinoma progression by increasing the expression of fibulin 5, 16 and UBE2T can also promote pyrimidine metabolism by enhancing Akt K63-linked ubiquitination, thus contributing to hepatocellular carcinoma (HCC) development. 17 …”

Section: Introductionmentioning

confidence: 99%

UBE2T Promotes Temozolomide Resistance of Glioblastoma Through Regulating the Wnt/β-Catenin Signaling Pathway

Wang¹,

Gao²,

Wei³

et al. 2023

DDDT

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Purpose Patients with glioblastoma (GBM) have poor prognosis and limited therapeutic options, largely because of chemoresistance to temozolomide (TMZ) treatment. Ubiquitin conjugating enzyme E2 T (UBE2T) plays a key role in regulating the malignancy of various tumors, including GBM; however, its role in TMZ resistance of GBM has not been elucidated. The purpose of this study was to clarify the role of UBE2T in mediating TMZ resistance and investigate the specific underlying mechanism. Methods Western blotting was used to detect the protein levels of UBE2T and Wnt/β-catenin-related factors. CCK-8, flow cytometry, and colony formation assays were used to examine the effect of UBE2T on TMZ resistance. Wnt/β-catenin signaling pathway activation was inhibited using XAV-939, and a xenograft mouse model was generated to clarify the function of TMZ in vivo. Results UBE2T knockdown sensitized GBM cells to TMZ treatment, whereas UBE2T overexpression promoted TMZ resistance. The specific UBE2T inhibitor, M435-1279, increased the sensitivity of GBM cells to TMZ. Mechanistically, our results demonstrated that UBE2T induces β-catenin nuclear translocation and increases the protein levels of downstream molecules, including survivin and c-Myc. Inhibition of Wnt/β-catenin signaling using XAV-939 blocked TMZ resistance due to UBE2T overexpression in GBM cells. In addition, UBE2T was shown to facilitate TMZ resistance by inducing Wnt/β-catenin signaling pathway activation in a mouse xenograft model. Combined treatment with TMZ and UBE2T inhibitor achieved superior tumor growth suppression relative to TMZ treatment alone. Conclusion Our data reveal a novel role of UBE2T in mediating TMZ resistance of GBM cells via regulating Wnt/β-catenin signaling. These findings indicate that targeting UBE2T has promising potential to overcome TMZ resistance of GBM.

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Deciphering potential molecular mechanisms in clear cell renal cell carcinoma based on the ubiquitin‐conjugating enzyme E2 related genes: Identifying UBE2C correlates to infiltration of regulatory T cells

Feng,

Wang,

Cen

et al. 2024

BioFactors

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Renal clear cell carcinoma (ccRCC) is a highly aggressive and common form of kidney cancer, with limited treatment options for advanced stages. Recent studies have highlighted the importance of the ubiquitin‐proteasome system in tumor progression, particularly the role of ubiquitin‐conjugating enzyme E2 (UBE2) family members. However, the prognostic significance of UBE2‐related genes (UBE2RGs) in ccRCC remains unclear. In this study, bulk RNA‐sequencing and single‐cell RNA‐sequencing data from ccRCC patients were retrieved from the Cancer Genome Atlas and Gene Expression Omnibus databases. Differential expression analysis was performed to identify UBE2RGs associated with ccRCC. A combination of 10 machine learning methods was applied to develop an optimal prognostic model, and its predictive performance was evaluated using area under the curve (AUC) values for 1‐, 3‐, and 5‐year overall survival (OS) in both training and validation cohorts. Functional enrichment analyses of gene ontology and Kyoto Encyclopedia of Genes and Genomes were conducted to explore the biological pathways involved. Correlation analysis was conducted to investigate the association between the risk score and tumor mutational burden (TMB) and immune cell infiltration. Immunotherapy and chemotherapy sensitivity were assessed by immunophenoscore and tumor immune, dysfunction, and exclusion scores to identify potential predictive significance. In vitro, knockdown of the key gene UBE2C in 786‐O cells by specific small interfering RNA to validate its impact on apoptosis, migration, cell cycle, migration, invasion of tumor cells, and induction of regulatory T cells (Tregs). Analysis of sc‐RNA revealed that UBE2 activity was significantly upregulated in malignant cells, suggesting its role in tumor progression. A three‐gene prognostic model comprising UBE2C, UBE2D3, and UBE2T was constructed by Lasoo Cox regression and demonstrated robust predictive accuracy, with AUC values of 0.745, 0.766, and 0.771 for 1‐, 3‐, and 5‐year survival, respectively. The model was validated as an independent prognostic factor in ccRCC. Patients in the high‐risk group had a worse prognosis, higher TMB scores, and low responsiveness to immunotherapy. Additionally, immune infiltration and chemotherapy sensitivity analyses revealed that UBE2RGs are associated with various immune cells and drugs, suggesting that UBE2RGs could be a potential therapeutic target for ccRCC. In vitro experiments confirmed that the reduction of UBE2C led to an increase in apoptosis rate, as well as a decrease in tumor cell invasion and metastasis abilities. Additionally, si‐UBE2C cells reduced the release of the cytokine Transforming Growth Factor‐beta 1 (TGF‐β1), leading to a decreased ratio of Tregs in the co‐culture system. This study presents a novel three‐gene prognostic model based on UBE2RGs that demonstrates significant predictive value for OS, immunotherapy, and chemotherapy in ccRCC patients. The findings underscore the potential of UBE2 family members as biomarkers and therapeutic targets in ccRCC, warranting further investigation in prospective clinical trials.

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UBE2T regulates epithelial–mesenchymal transition through the PI3K-AKT pathway and plays a carcinogenic role in ovarian cancer

Cited by 7 publications

References 57 publications

Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

UBE2T Promotes Temozolomide Resistance of Glioblastoma Through Regulating the Wnt/β-Catenin Signaling Pathway

Deciphering potential molecular mechanisms in clear cell renal cell carcinoma based on the ubiquitin‐conjugating enzyme E2 related genes: Identifying UBE2C correlates to infiltration of regulatory T cells

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