UBE2T promotes glioblastoma malignancy through ubiquitination-mediated degradation of RPL6,Cancer Science

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UBE2T promotes glioblastoma malignancy through ubiquitination-mediated degradation of RPL6
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-26 , DOI: 10.1111/cas.15604
Xuxiu Tao _{1,

2} , Xia Wu _{2,

3} , Peijun Zhou _{1,

2} , Xuehui Yu _{1,

2} , Chen Zhao _{1,

2} , Xingzhi Peng _{1,

2} , Kun Zhang ₁ , Liangfang Shen ₁ , Jinwu Peng _{4,

5} , Lifang Yang _{1,

2}

Affiliation

Glioblastoma (GBM) is the most frequent and aggressive malignant glioma. Due to patients’ poor prognosis, it is of great clinical significance to determine new targets that may improve GBM treatment. In the present study, we showed that ubiquitin (Ub)-conjugating enzyme E2T (UBE2T) was significantly overexpressed in GBM and could promote proliferation, invasion, and inhibit apoptosis of GBM cells. Mechanistically, UBE2T functioned as the Ub enzyme of ribosomal protein L6 (RPL6) and induced the ubiquitination and degradation of RPL6 in an E3 ligase-independent manner through direct modification by K48-linked polyubiquitination, thus contributing to the malignant progression of GBM cells. Furthermore, inhibiting the expression of RPL6 by UBE2T could not only reduce the expression of wild-type p53, but also enhance the gain-of-function of mutant p53. Moreover, knockdown of UBE2T in LN229 cells obviously suppressed tumor growth in LN229 xenograft mouse models. Collectively, our study demonstrated that UBE2T promotes GBM malignancy through ubiquitination-mediated degradation of RPL6 regardless of the p53 mutation status. It will provide new candidates for molecular biomarkers and therapeutic targets for clinical application in GBM.

中文翻译：

UBE2T 通过泛素化介导的 RPL6 降解促进胶质母细胞瘤恶性

胶质母细胞瘤（GBM）是最常见和最具侵袭性的恶性胶质瘤。由于患者预后较差，确定可能改善GBM治疗的新靶点具有重要的临床意义。在本研究中，我们发现泛素（Ub）结合酶E2T（UBE2T）在GBM中显着过表达，并且可以促进GBM细胞的增殖、侵袭和抑制凋亡。从机制上讲，UBE2T充当核糖体蛋白L6（RPL6）的Ub酶，并通过K48连接的多聚泛素化直接修饰，以E3连接酶独立的方式诱导RPL6泛素化和降解，从而促进GBM细胞的恶性进展。此外，UBE2T抑制RPL6的表达不仅可以减少野生型p53的表达，还可以增强突变型p53的功能获得。此外，LN229细胞中UBE2T的敲低明显抑制了LN229异种移植小鼠模型中的肿瘤生长。总的来说，我们的研究表明，无论 p53 突变状态如何，UBE2T 通过泛素化介导的 RPL6 降解促进 GBM 恶性肿瘤。它将为 GBM 的临床应用提供新的分子生物标志物候选物和治疗靶点。

更新日期：2022-09-26

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