A homozygous missense variant in UBE2T is associated with a mild Fanconi anemia phenotype

Schultz‐Rogers, Laura; Lach, Francis P.; Rickman, Kimberly A.; Ferrer, Alejandro; Mangaonkar, Abhishek A.; Schwab, Tanya L.; Schmitz, Christopher T.; Clark, Karl J.; Dsouza, Nikita R.; Zimmermann, Michael T.; Litzow, Mark R.; Jacobi, Nicole; Klee, Eric W.; Smogorzewska, Agata; Patnaik, Mrinal M.

doi:10.3324/haematol.2020.259275

Cited by 3 publications

(1 citation statement)

References 14 publications

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“… 7 UBE2T was initially reported as a negative regulator of the Fanconi anemia (FA) pathway; its deletion leads to impaired DNA repair ability and the formation of abnormal chromosomes, which are a feature of FA. 8 , 9 In addition to its relevance in FA, UBE2T also has vital roles in the development, progression, and recurrence of various tumors. 10–14 UBE2T facilitates the occurrence and development of ovarian cancer by regulating epithelial–mesenchymal transition (EMT) through the PI3K-AKT pathway.…”

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confidence: 99%

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

Wang¹,

Gao²,

Wei³

et al. 2023

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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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