UBE2S, a novel substrate of Akt1, associates with Ku70 and regulates DNA repair and glioblastoma multiforme resistance to chemotherapy.
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.
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.|State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.
L
L
Hu
Department of Neurosurgery, Liaocheng People's Hospital of Shandong University, Liaocheng, China.
X
X
Li
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.
Q
Q
Liu
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
J
J
Xu
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
H
H
Ge
Department of Epidemiology and Biostatistics, Harbin Medical University, Harbin, China.
Z
Z
Wang
Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
H
H
Wang
Saint-Antoine Research Centre, University Pierre and Marie CURIE, Paris, France.
Z
Z
Wang
Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
C
C
Shi
Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China.
X
X
Xu
Department of Neurosurgery, University of Florida, Gainesville, USA.
J
J
Huang
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Z
Z
Lin
Department of Neurological Surgery, University of California, San Francisco, USA.
R O
RO
Pieper
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.
C
C
Weng
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D025801:Ubiquitin; D005047:Etoposide; C544962:Ube2S protein, human; D044763:Ubiquitin-Conjugating Enzymes; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000072200:Ku Autoantigen