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

Hou, Jingyao; Deng, Qing; Zhou, Jinyuan; Zou, Jiahua; Zhang, Y; Tan, Puay‐Hoon; Zhang, W; Cui, Hongjuan

doi:10.1038/onc.2016.280

Cited by 80 publications

(90 citation statements)

References 33 publications

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“…CSN6, another subunit of COP9 family, exhibits similar structures as CSN5 and also interact by the MPN domain 22 . Overexpression of CSN6 in GBM has been shown to be associated with tumor progression 23 . CSN6 contributed to Myc stability through the CSN‐Cullin‐Fbxw7 axis during tumorigenesis in breast and pancreatic cancers 24 .…”

Section: Introductionmentioning

confidence: 99%

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Guo

Lou

et al. 2020

Molecular Carcinogenesis

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Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD‐L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR‐ERK pathway regulates CSN6 for PD‐L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD‐L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD‐L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD‐L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF‐upregulated p‐EGFR, p‐ERK, CSN6, and PD‐L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD‐L1 in EGF‐treated cells. Inhibition of CSN6 by small interfering RNA decreased PD‐L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF‐reduced CHX‐induced CSN6 and PD‐L1 turnover in GBM cells. Furthermore, CSN6‐mediated downregulation of PD‐L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR‐ERK pathway may upregulate CSN6, which may inhibit PD‐L1 degradation and subsequently maintain PD‐L1 stability in GBM.

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Section: Introductionmentioning

confidence: 99%

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Guo

Lou

et al. 2020

Molecular Carcinogenesis

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“…We found that CSN6 greatly affected the protein expression of cyclin D, CDK4 and p16 ( Figure 3A ). Previous studies have found that the expression of CDK4 and cyclin D was reduced in the CSN6-knockdown cells 19 . It is well known that the p16 and p21 proteins are cyclin-dependent kinase inhibitors.…”

Section: Resultsmentioning

confidence: 83%

“…The CSN mediates a variety of cellular functions through its association with cullin-containing ubiquitin E3 ligases 11,16 . Previous studies have suggested that CSN6 associates with aberrant gene regulators such as MEK kinase 1 (MEKK1), E6-associated protein (E6AP) and epidermal growth factor receptor (EGFR) by facilitating ubiquitin-mediated degradation 17-19 . Moreover, CSN6 stabilizes COP1 through reducing COP1 self-ubiquitination and the CSN6-COP1 axis function as an E3 ubiquitin ligase involved in 14-3-3σ degradation to regulate cell growth and tumorigenicity 10,20 .…”

Section: Introductionmentioning

confidence: 99%

CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16INK4a

Liu

Zhu

et al. 2019

Cancer Biol Med

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Objective: CSN6 is a vital subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is responsible for development disorders and promotes ubiquitin-26S proteasome-dependent degradation in vitro and vivo. Its role in the tumor development of gastric cancer remains unclear. In this study, we investigated the role of CSN6 in gastric cancer progression. Methods: Human gastric cancer samples were collected and immunohistochemistry was performed to identify the role of CSN6 in gastric cancer. The cell proliferation was measured by CCK-8 and the EdU incorporation method. Immunofluorescence localization and a co-immunoprecipitation study were used to show the interaction between the protein CSN6 and p16. Ubiquitination assay was performed to validate whether ubiquitination is involved in CSN6-mediated p16 degradation. BALB/c nude mice were used to produce a tumor model in order to test the effect of CSN6 on cancer growth in vivo. Results: CSN6 expression was dramatically increased in gastric cancer tissues compared with paired adjacent non-tumor tissues and CSN6 was correlated with worse overall and disease-specific survival. Additionally, we also found that CSN6 downregulated p16 protein expression, thereby promoting gastric cancer cell growth and proliferation. Moreover, CSN6 interacted with p16 and a proteasome activator REGγ (PA28γ), thereby facilitating ubiquitin-independent degradation of p16. Conclusions: CSN6 promoted the loss of p16-mediated tumor progression and played an important role in regulating ubiquitin-independent proteasomal degradation of p16.

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“…These data indicated that CSN6 is involved in AR intracellular trafficking. Moreover, it was previously reported that CSN6 interacts with Erk, to down regulate the EGFR signaling pathway [15]. The activation of this pathway is critical for the release of the sperm from Sertoli cells, and for blood-testis barrier integrity [20].…”

Section: Discussionmentioning

confidence: 99%

“…CSN6 reportedly controls the proliferation and metastasis of glioblastoma by chromatin immunoprecipitation-mediated degradation of epidermal growth factor receptor (EGFR) [15], extracellular regulated protein kinases (Erk)1/2-dependent phosphorylation of CSN6 is critical in colorectal cancer development [16]. We examined whether CSN6 is involved in Fig.…”

Section: Csn6 Knockdown Down-regulate Phosphorylation Signaling Pathwaymentioning

confidence: 99%

CSN6 and Rab34 Are Involved in Androgen Receptor Trafficking in Mouse Testicular Sertoli Cells

Deng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Androgen and its receptor (AR) play an important role in maintaining spermatogenesis and male fertility. Our previous studies showed that testosterone at a physiological concentration induces cytoplasmic AR translocation to the Sertoli cell plasma membrane of within 5 minutes. Methods: In this study, mass spectrometry (MS) and bioinformatic analyses were applied to identify candidate proteins mediating AR trafficking. The candidate proteins were knocked down by shRNA transfection. Results: Nine candidate proteins were identified by MS. The data was verified by co-immunoprecipitation and Western blot. Of the candidates, CSN6 regulated AR transport through the phosphorylation signaling pathway and Rab34 affected AR trafficking by regulating Ras activity. Conclusions: CSN6 and Rab34 are involved in AR trafficking by regulating the phosphorylation signaling pathway. These findings provide new insights into the testosterone signaling pathway in Sertoli cells that mediates spermatogenesis.

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

Cited by 80 publications

References 33 publications

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16INK4a

CSN6 and Rab34 Are Involved in Androgen Receptor Trafficking in Mouse Testicular Sertoli Cells

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