ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

Fang, Lekun; Lu, Weisi; Choi, Hyun Ho; Yeung, Sai Ching Jim; Tung, Jung-Yu; Hsiao, Chwan‐Deng; Fuentes‐Mattei, Enrique; Menter, David G.; Chen, Chuangqi; Wang, Lei; Wang, Jianping; Lee, Mong Hong

doi:10.1016/j.ccell.2015.07.004

Cited by 65 publications

(93 citation statements)

References 55 publications

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“…For instance, deubiquitination of HSP70 and Snail by CSN5 were reported to modulate exosomal protein sorting (Liu et al, 2009) and to enhance cancer cell invasion and migration (Wu et al, 2009), respectively. Recently, phosphorylation of CSN6 by ERK was found to stabilize β-catenin for colon cancer cell proliferation (Fang et al, 2015). These results demonstrated that the deubiquitination activity of the CSN family is crucial for cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Deubiquitination and Stabilization of PD-L1 by CSN5

et al. 2016

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SUMMARY Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.

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Section: Introductionmentioning

confidence: 99%

Deubiquitination and Stabilization of PD-L1 by CSN5

et al. 2016

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“…CSN6 contributed to Myc stability through the CSN‐Cullin‐Fbxw7 axis during tumorigenesis in breast and pancreatic cancers 24 . CSN6 could also regulate β‐catenin stability by regulating ubiquitination in colorectal cancer 25 . EGFR‐ERK‐related pathways have been shown to regulate CSN6 expression to stabilize β‐catenin 25 .…”

Section: Introductionmentioning

confidence: 99%

“…CSN6 could also regulate β‐catenin stability by regulating ubiquitination in colorectal cancer 25 . EGFR‐ERK‐related pathways have been shown to regulate CSN6 expression to stabilize β‐catenin 25 . In addition, EGF could upregulate the expression of B3GNT3 to enhance the stability of PD‐L1 protein in triple‐negative breast cancer 26 .…”

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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“…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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ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

Cited by 65 publications

References 55 publications

Deubiquitination and Stabilization of PD-L1 by CSN5

Deubiquitination and Stabilization of PD-L1 by CSN5

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

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

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