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

Oncogene volume 36, pages 1145–1156 (2017)Cite this article

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Abstract

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.

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Acknowledgements

We are grateful to Dr Vera Gorbunova for providing the pEGFP-Pem1-Ad2 system. We thank Jane Gordon and Qimeng Tao for technical support. We thank Dr Lei Pan, Dr Changbin Shi for their critical review of the article. This work was supported by the National Natural Science Foundation of China (81372721); International Science & Technology Cooperation Program of China (2014DFA31630); Specialized Research Fund for the Doctoral Program of Higher Education (20132307110029) and National Cancer Institute (R01 CA171610T).

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    L Hu, H Ge & Z Lin

  2. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China

    L Hu, Q liu & C Weng

  3. Department of Neurosurgery, Liaocheng People’s Hospital of Shandong University, Liaocheng, China

    X Li

  4. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China

    J Xu

  5. Department of Epidemiology and Biostatistics, Harbin Medical University, Harbin, China

    Z Wang

  6. Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    H Wang

  7. Saint-Antoine Research Centre, University Pierre and Marie CURIE, Paris, France

    Z Wang

  8. Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    C Shi

  9. Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China

    X Xu

  10. Department of Neurosurgery, University of Florida, Gainesville, USA

    J Huang

  11. Department of Neurological Surgery, University of California, San Francisco, USA

    R O Pieper

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Hu, L., Li, X., liu, Q. et al. UBE2S, a novel substrate of Akt1, associates with Ku70 and regulates DNA repair and glioblastoma multiforme resistance to chemotherapy. Oncogene 36, 1145–1156 (2017). https://doi.org/10.1038/onc.2016.281

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