UBE2T promotes glioblastoma malignancy through ubiquitination-mediated degradation of RPL6.
UBE2T promotes glioblastoma malignancy through ubiquitination-mediated degradation of RPL6.
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胶质母细胞瘤(GBM)是最常见、最具侵袭性的恶性胶质瘤。由于患者预后较差，寻找新的靶点可能改善GBM的治疗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中高表达，并能促进GBM细胞的增殖、侵袭和抑制凋亡。在机制上，UBE2T作为核糖体蛋白L6(RPL6)的Ub酶，通过K48连接的多泛素化的直接修饰，诱导RPL6以不依赖E3连接酶的方式泛素化和降解，从而促进GBM细胞的恶性进展。此外，通过UBE2T抑制RPL6的表达，不仅可以降低野生型P53的表达，而且还可以增强突变型P53的功能获得。此外，UBE2T在LN229细胞中的敲除明显抑制了LN229移植瘤小鼠模型的肿瘤生长。总之，我们的研究表明，UBE2T通过泛素化介导的RPL6降解促进了GBM的恶性，而与P53突变状态无关。为临床应用提供了新的分子生物学标志物和治疗靶点。本研究表明，UBE2T过表达促进了GBM细胞的增殖、侵袭和抗凋亡作用。进一步发现，UBE2T通过泛素化修饰抑制RPL6的表达，从而促进无论是突变型还是野生型p53的GBM恶性转化。
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. The present study showed that overexpression of UBE2T promoted the proliferation, invasion and anti‐apoptosis of GBM cells. It is further discovered that UBE2T inhibited the expression of RPL6 through ubiquitination modification, thereby promoting the GBM malignance no matter p53 was mutation or wild status.
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