Ubiquitin-conjugating enzyme E2T(UBE2T) promotes colorectal cancer progression by facilitating ubiquitination and degradation of p53

Wu, Mengqiong; Li, Xianglu; Huang, Weiwei; Chen, Yiming; Wang, Baochun; Liu, Xin

doi:10.1016/j.clinre.2020.06.018

Cited by 18 publications

(17 citation statements)

References 39 publications

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“…The oncogene protein ubiquitin-conjugating enzyme E2T (UBE2T) is a ubiquitin-conjugating enzyme (E2) which was widely reported to be upregulated and promotes tumorigenesis, proliferation, and metastasis in various cancers in an E2 activitydependent manner [5][6][7][8][9]. For example, UBE2T promoted the proliferation of breast cancer cells via ubiquitinating and downregulating BRCA1 [6].…”

Section: Introductionmentioning

confidence: 99%

UBE2T-mediated Akt ubiquitination and Akt/β-catenin activation promotes hepatocellular carcinoma development by increasing pyrimidine metabolism

et al. 2022

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The oncogene protein ubiquitin-conjugating enzyme E2T (UBE2T) is reported to be upregulated in hepatocellular carcinoma (HCC) and correlated with poor clinical outcomes of HCC patients. However, the underlying mechanism by which UBE2T exerts its oncogenic function in HCC remains largely unexplored. In this study, in vitro and in vivo experiments suggested that UBE2T promoted HCC development including proliferation and metastasis. GSEA analysis indicated that UBE2T was positively correlated with pyrimidine metabolism, and LC/MS-MS metabolomics profiling revealed that the key products of pyrimidine metabolism were significantly increased in UBE2T-overexpressing cells. UBE2T overexpression led to the upregulation of several key enzymes catalyzing de novo pyrimidine synthesis, including CAD, DHODH, and UMPS. Moreover, the utilization of leflunomide, a clinically approved DHODH inhibitor, blocked the effect of UBE2T in promoting HCC progression. Mechanistically, UBE2T increased Akt K63-mediated ubiquitination and Akt/β-catenin signaling pathway activation. The disruption of UBE2T-mediated ubiquitination on Akt, including E2-enzyme-deficient mutation (C86A) of UBE2T and ubiquitination-site-deficient mutation (K8/14 R) of Akt impaired UBE2T’s effect in upregulating CAD, DHODH, and UMPS. Importantly, we demonstrated that UBE2T was positively correlated with p-Akt, β-catenin, CAD, DHODH, and UMPS in HCC tumor tissues. In summary, our study indicates that UBE2T increases pyrimidine metabolism by promoting Akt K63-linked ubiquitination, thus contributing to HCC development. This work provides a novel insight into HCC development and a potential therapeutic strategy for HCC patients.

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Section: Introductionmentioning

confidence: 99%

UBE2T-mediated Akt ubiquitination and Akt/β-catenin activation promotes hepatocellular carcinoma development by increasing pyrimidine metabolism

et al. 2022

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“…According to other studies, UBE2T expression is also upregulated in other types of tumor, including gastric, lung, prostate, nasopharyngeal and bladder cancer (24)(25)(26)(27). However, few studies have examined the association between UBE2T and CRC; one study has reported that UBE2T may promote CRC progression (28). Based on previous reports, we speculated that the role of UBE2T may be similar in different types of tumor and that UBE2T could be involved in the development and progression of CRC.…”

Section: Discussionmentioning

confidence: 78%

Expression of ubiquitin‑conjugating enzyme E2T in colorectal cancers and clinical implications

Liu

et al. 2020

Oncol Lett

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Ubiquitin-conjugating enzyme E2T (UBE2T) plays a significant role in carcinogenesis. Previous studies have demonstrated that UBE2T promotes the development and progression of numerous types of cancer. However, the association between UBE2T expression and colorectal cancer (CRC) remains unclear. In the present study, UBE2T protein expression was examined in the tissues of patients with CRC via immunohistochemistry. In addition, UBE2T expression data and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA). In the clinical samples, the associations between UBE2T expression and clinicopathological factors were evaluated by the χ 2 or Fisher's exact tests. In TCGA data, associations between UBE2T expression and clinical characteristics were evaluated using a logistic regression model. Overall survival was analyzed using Kaplan-Meier and Cox regression analyses. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting assays were used to examine UBE2T expression in normal and CRC cell lines. Gene set enrichment analysis (GSEA) was performed on the dataset from TCGA. UBE2T protein was highly expressed in the cytoplasm of tumor cells in 29/50 clinical samples, whereas in the adjacent normal tissues, it was only highly expressed in 2/50 samples. Furthermore, UBE2T expression was associated with the N classification (P<0.001), clinical TNM stage (P<0.001) and histological grade of tumors (P=0.010). Survival analysis showed an association between high UBE2T expression and poor survival rate in patients with CRC (P=0.002). Cox regression analysis also revealed that UBE2T expression was an independent prognostic factor for these patients (P=0.006). RT-qPCR and western blotting showed that UBE2T was expressed in CRC cell lines at higher levels than that in a normal colon cell line. Analysis of TCGA data revealed that UBE2T was highly expressed in tumor samples compared with normal samples, but was not associated with prognosis. GSEA showed that high expression of UBE2T was associated with the Kyoto Encyclopedia of Genes and Genomes pathways ‘cell cycle’, ‘oxidative phosphorylation’, ‘DNA replication’, ‘p53 signaling pathway’, ‘ubiquitin mediated proteolysis’ and ‘pentose phosphate pathway’. These results indicate that UBE2T may play an important role in the progression of CRC and serve as a potential prognostic factor during the treatment of cancer.

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“…UBE2T enhances nasopharyngeal carcinoma cell multiplication and invasion by activating the AKT/GSK3β/β-catenin pathway [ 17 ]. Additionally, UBE2T modulates cancer progression by enhancing p53 ubiquitination and degradation in colorectal cancer and HCC [ 6 , 10 , 18 ]. Wnt/β-catenin signaling pathway is one of the key cascades in regulating physiological and pathological processes, such as cell proliferation and differentiation, stem cell renewal, embryogenesis, and tissue homeostasis [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…UBE2T overexpression is reported to lead to unfavorable prognosis in patients with gallbladder cancer and UBE2T can be used as an independent prognostic biomarker for patients with gallbladder cancer [ 5 ]. UBE2T overexpression facilitates the growth, proliferation, and invasion of colorectal cancer cells and suppresses apoptosis [ 6 ]. Nonetheless, the role of UBE2T in HCC and its regulatory mechanisms need to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of ubiquitin-conjugating enzyme E2T (UBE2T) predicts poor prognosis and promotes hepatocellular carcinoma progression

Ren

Ying

et al. 2021

Bioengineered

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Reportedly, ubiquitin-conjugating enzyme E2T (UBE2T) is closely related to the progression of several malignancies. This work is aimed to probe the role of UBE2T in the progression of hepatocellular carcinoma (HCC) patients. The microarray analysis was executed to screen the differentially expressed genes (DEGs) in HCC tissues. The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases, PCR and immunohistochemistry were utilized to validate the dysregulation of UBE2T in HCC. Kaplan-Meier analysis was employed to determine the relationship between UBE2T expression and the prognosis of HCC patients. PCR was carried out to detect UBE2T protein expression in HCC cell lines. Cell Counting Kit-8 (CCK-8) assay and 5-bromo-2 -deoxyuridine (BrdU) experiments were conducted to examine the proliferation of HCC cells. Scratch healing and Transwell experiments were conducted to examine the migration of HCC cells. Bioinformatics analysis and dual-luciferase reporter gene experiments predicted and validated the targeting relationship with miR-212-5p and UBE2T. We found that UBE2T expression was remarkably up-modulated in HCC tissues and cell lines, and its high expression was linked to a worse prognosis in HCC patients. UBE2T overexpression enhanced HCC cell proliferation and migration. Additionally, UBE2T was verified as a downstream target of miR-212-5p. In conclusion, UBE2T overexpression is markedly linked to unfavorable prognosis in HCC patients. UBE2T, regulated by miR-212-5p, significantly enhances the malignant phenotypes of HCC cells, which can be used as a target for HCC diagnosis and prognosis.

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Ubiquitin-conjugating enzyme E2T(UBE2T) promotes colorectal cancer progression by facilitating ubiquitination and degradation of p53

Cited by 18 publications

References 39 publications

UBE2T-mediated Akt ubiquitination and Akt/β-catenin activation promotes hepatocellular carcinoma development by increasing pyrimidine metabolism

UBE2T-mediated Akt ubiquitination and Akt/β-catenin activation promotes hepatocellular carcinoma development by increasing pyrimidine metabolism

Expression of ubiquitin‑conjugating enzyme E2T in colorectal cancers and clinical implications

Upregulation of ubiquitin-conjugating enzyme E2T (UBE2T) predicts poor prognosis and promotes hepatocellular carcinoma progression

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