UBE2S, a novel substrate of Akt1, associates with Ku70 and regulates DNA repair and glioblastoma multiforme resistance to chemotherapy
UBE2S, a novel substrate of Akt1, associates with Ku70 and regulates DNA repair and glioblastoma multiforme resistance to chemotherapy
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UBE2S 是 Akt1 的一种新型底物，与 Ku70 结合并调节 DNA 修复和多形性胶质母细胞瘤对化疗的耐药性
DOI：
10.1038/onc.2016.281
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发表时间：
2017-02-23
期刊：
影响因子：
8
通讯作者：
Weng, C.
中科院分区：
文献类型：
--
作者：
Hu, L.;Li, X.;Weng, C.
多形性胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑癌。然而，致癌的分子基础事件及其相互作用仍然难以捉摸。在这里，我们报告，泛素结合酶E2 S（UBE 2S）的稳定性是由PTEN/Akt途径调节，其降解依赖于泛素-蛋白酶体系统。从机制上讲，Akt 1与UBE 2S在Thr 152处发生物理相互作用并磷酸化，通过抑制蛋白酶体降解增强其稳定性。此外，积累的UBE 2S被发现与非同源末端连接（NHEJ）复合物的组分相关，并参与NHEJ介导的DNA修复过程。Ku 70与UBE 2S的结合增强，并且该复合物被募集到双链断裂（DSB）位点以响应依托泊苷治疗。此外，UBE 2S表达的敲低抑制NHEJ介导的DSB修复，并使胶质母细胞瘤细胞对化疗更敏感。总的来说，我们的研究结果提供了一个新的药物靶点，可以作为开发新的治疗方法的基本原理。
Glioblastoma multiforme (GBM) is the most common primary malignant brain cancer in adults. However, the molecular events underlying carcinogenesis and their interplay remain elusive. Here, we report that the stability of Ubiquitin-conjugating enzyme E2S (UBE2S) is regulated by the PTEN/Akt pathway and that its degradation depends on the ubiquitin-proteasome system. Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation. Additionally, accumulated UBE2S was found to be associated with the components of the non-homologous end-joining (NHEJ) complex and participated in the NHEJ-mediated DNA repair process. The association of Ku70 with UBE2S was enhanced, and the complex was recruited to double-stranded break (DSB) sites in response to etoposide treatment. Furthermore, knockdown of UBE2S expression inhibited NHEJ-mediated DSB repair and rendered glioblastoma cells more sensitive to chemotherapy. Overall, our findings provide a novel drug target that may serve as the rationale for the development of a new therapeutic approach.