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

Abstract

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.

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

“…In addition, an association between the WNT signaling pathway and OSCC prognosis has been established [ 45 – 52 ], positioning it as an independent prognostic factor [ 16 , 53 , 54 ]. The role of WNT/β-catenin activation in mediating chemoresistance in other cancers has also been confirmed in the emerging literature [ 18 , 55 , 56 ], in which WNT/β-catenin activation supports 5FU-resistance through mechanisms such as cancer stem cell, metastasis, and enhanced transcriptional activity [ 19 , 57 – 59 ].…”

“…Although there have been many studies on the mechanism of 5FU-resistance, it still remains unclear. In recent years, the Wingless and Int-1 (WNT)/β-catenin signaling pathway has received more and more attention in the study of drug resistance [ 15 – 19 ]. The WNT/β-catenin pathway is activated by ligands such as WNT1, WNT3, WNT3A, WNT8A, WNT10A, and WNT10B, and then β-catenin enters the nucleus and binds to the transcription factor TCF/LEF, thus regulating the expression of downstream target genes such as c-Myc, cyclin D1, and AXIN2 [ 20 – 22 ].…”

“…The WNT/β-catenin pathway is activated by ligands such as WNT1, WNT3, WNT3A, WNT8A, WNT10A, and WNT10B, and then β-catenin enters the nucleus and binds to the transcription factor TCF/LEF, thus regulating the expression of downstream target genes such as c-Myc, cyclin D1, and AXIN2 [ 20 – 22 ]. Studies have shown that abnormal activation of the WNT signaling pathway is closely related to the proliferation [ 23 ], invasion [ 24 ], metastasis [ 15 , 16 , 25 ], and drug resistance [ 26 – 28 ] of OSCC [ 17 – 19 ], and is a potential therapeutic target [ 29 ]. Previous studies have highlighted the effect of β-catenin on drug resistance, however, more evidence is needed to explore the effects of WNT ligands, the “switches” for pathway activation, on drug resistance.…”

The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

“…The recognition of the role of ubiquitination enzymes in chemotherapeutic resistance has been growing alongside the increasing number of studies conducted on these enzymes in various cancers. A notable example is the promotion of resistance to cisplatin in non-small cell lung cancer through TRIM17-mediated ubiquitination and degradation of RBM38 (Zhong et al 2023 );RNF6 promotes cisplatin resistance by transcriptionally activating the expression of proliferating cell nuclear antigens and attenuating DNA damage in lung adenocarcinoma (Sun et al 2022 ).In addition, UBE2T promotes temozolomide resistance in glioblastoma by modulating the Wnt/β-catenin signaling pathway (Wang et al 2023 ). The results of these experiments may provide insights into the mechanisms of chemoresistance of these ubiquitination enzymes in CRC.…”

Role of UBE2C in Brain Cancer Invasion and Dissemination

“…Interestingly, a high-throughput small interfering RNA (siRNA) screen in T98G glioma cells reported that 22% of the genes identified as being crucial for GB survival encoded for components of the proteasome subunits 20S and 26S [36]. Moreover, aberrant levels of different E2 and E3 enzymes have been reported in glioma, having either oncogenic or antitumoral effects [37][38][39][40]. On the other hand, altered levels of deubiquitinating enzymes (DUBs), which enhance protein stability by cleaving the ubiquitin and thus reversing ubiquitinmediated proteolysis, can also affect crucial signaling pathways and consequently lead to malignancies.…”