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.