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

Oncogene. 2017 Feb 23;36(8):1134-1144. doi: 10.1038/onc.2016.280. Epub 2016 Aug 22.


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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis
  • Biomarkers, Tumor
  • COP9 Signalosome Complex
  • Cell Movement*
  • Cell Proliferation*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Staging
  • Prognosis
  • Protein Stability
  • Signal Transduction
  • Tumor Cells, Cultured
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Xenograft Model Antitumor Assays


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • COPS6 protein, human
  • Ubiquitin
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases
  • EGFR protein, human
  • ErbB Receptors
  • COP9 Signalosome Complex