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CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR

Oncogene volume 36, pages 1134–1144 (2017)Cite this article

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Abstract

CSN6, a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has received attention as a regulator of the degradation of cancer-related proteins such as p53, c-myc and c-Jun, through the ubiquitin-proteasome system, suggesting its importance in cancerogenesis. However, the biological functions and molecular mechanisms of CSN6 in glioblastoma (GBM) remain poorly understood. Here, we report that GBM tumors overexpressed CSN6 compared with normal brain tissues and that CSN6 promoted GBM cell proliferation, migration, invasion and tumorigenesis. Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was used to reveal that the proliferative and metastatic effects of CSN6 on GBM cells were EGFR dependent. We also found that CSN6 positively regulated EGFR stability via reduced levels of EGFR ubiquitination, thereby elevating steady expression of EGFR. In addition, this study is the first description of a novel role for the CSN6-interacting E3 ligase, CHIP (carboxyl terminus of heat-shock protein 70-interacting protein), regulating EGFR ubiquitination in cancer cells. We showed that CSN6 associated with CHIP and led to CHIP destabilization by increasing CHIP self-ubiquitination. Moreover, CSN6 decreased CHIP expression and increased EGFR expression in the tumor samples. Deregulation of this axis promoted GBM cell’s proliferation and metastasis. Thus, our study provides insights into the applicability of using the CSN6-CHIP-EGFR axis as a potential therapeutic target in cancer.

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Acknowledgements

This work was supported by the Research Fund for the Doctoral Program of Higher Education of China (20130182110003), the National Basic Research Program of China (No. 2012cb114603) and the National Natural Science Foundation of China (81502574 and 31501100).

Author contributions

JH: Collection and assembly of data, data analysis and interpretation and manuscript writing; QD and JZ: collection and assembly of data and data analysis; JZ, YZ, PT and WZ: collection and assembly of data; HC: concept design, financial support, data analysis and interpretation and manuscript revision.

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Authors and Affiliations

  1. Cell Biology Laboratory, State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China

    J Hou, Q Deng, J Zou, Y Zhang, P Tan, W Zhang & H Cui

  2. Department of Neurosurgery, Rocket Force General Hospital, Chinese People’s Liberation Army, Beijing, China

    J Zhou

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  1. J Hou
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Correspondence to H Cui.

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Hou, J., Deng, Q., Zhou, J. et al. CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. Oncogene 36, 1134–1144 (2017). https://doi.org/10.1038/onc.2016.280

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  • DOI: https://doi.org/10.1038/onc.2016.280

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