UBE2S, a novel substrate of Akt1, associates with Ku70 and regulates DNA repair and glioblastoma multiforme resistance to chemotherapy

• Published in: Oncogene Vol. 36; no. 8; pp. 1145 - 1156
• Main Authors: Hu, L, Li, X, Liu, Q, Xu, J, Ge, H, Wang, Z, Wang, H, Shi, C, Xu, X, Huang, J, Lin, Z, Pieper, R O, Weng, C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.02.2017
• Subjects: AKT protein; AKT1 protein; Analysis; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain cancer; Brain tumors; Cancer; Carcinogenesis; Care and treatment; Cell Proliferation - drug effects; Chemotherapy; Deoxyribonucleic acid; Diagnosis; DNA; DNA Damage - drug effects; DNA Damage - genetics; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; Drug Resistance, Neoplasm - genetics; Etoposide; Etoposide - pharmacology; Female; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma cells; Glioblastoma multiforme; Health aspects; Humans; Ku Autoantigen - genetics; Ku Autoantigen - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Non-homologous end joining; Patient outcomes; Phosphorylation; Proteasomes; Protein expression; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; PTEN protein; Risk factors; Signal transduction; Therapeutic targets; Tumor Cells, Cultured; Tumorigenesis; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-conjugating enzyme; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Xenograft Model Antitumor Assays; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.281

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.