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

Du, Wen‐Qi; Liu, Zongxiang; Zhu, Wentao; Li, Tongtong; Zhu, Zhansheng; Wei, Lulu; Song, Jun; Pei, Dong‐Sheng

doi:10.20892/j.issn.2095-3941.2018.0410

Cited by 13 publications

(7 citation statements)

References 49 publications

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“…Thus, aberrant expression of COPS subunits may contribute to cancer development and progression. Indeed, COPS subunit overexpression has been detected in breast cancer [ 40 – 42 ], HCC [ 18 , 43 ], colorectal cancer [ 44 ], gastric cancer [ 23 , 45 ], pancreatic cancer [ 46 , 47 ], myeloma [ 48 ], non-small cell lung cancer [ 49 ], prostate cancer [ 50 ], and osteosarcoma [ 51 ]. Overexpression of COPS5 has also been implicated in lymph node metastasis [ 52 ] and histological tumor progression [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma

Liu,

Han,

Xuan

et al. 2024

Aging

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Hepatocellular carcinoma (HCC) is among the most common deadly tumors but still lacks specific biomarkers for diagnosis, prognosis, and treatment guidance. The COP9 signalosome (COPS) is an essential regulator of the ubiquitin conjugation pathway upregulated in various cancers. We evaluated the contributions of COPS subunits to HCC tumorigenesis and their utility for prognosis. We comprehensively evaluated the tumor expression pattern and tumorigenic functions of COPS subunits using The Cancer Genome Atlas (TCGA), The Human Protein Atlas and immunohistochemistry. Kaplan–Meier, Cox regression, ROC curve, and nomogram analyses were used to assess the predictive values of COPS subunits for clinical outcome. Expression levels of COPS subunits were significantly upregulated in HCC tissues, which predicted shorter overall survival (OS). Further, Cox regression analysis identified COPS5, COPS7B, and COPS9 as independent prognostic biomarkers for OS. High mutation rates were also found in COPS subunits. Functional network analysis indicated that COPS and neighboring genes regulate ‘protein neddylation’, ‘protein deneddylation’, and ‘protein ubiquitination’. The COPS PPI included strong interactions with p53, CUL1/2/3/4, and JUN. Moreover, the correlations between COPS subunit expression levels and tumor immune cell infiltration rates were examined using TIMER, TISIDB, ssGSEA, and ESTIMATE packages. COPS subunits expression levels were positively correlated with specific tumor immune cell infiltration rates, immunoregulator expression levels, and microsatellite instability in HCC. Finally, knockout of COPS6 and COPS9 in HCC cells reduced while overexpression enhanced proliferation rate and metastasis capacity. Our study revealed that COPS potential biomarker for unfavorable HCC prognosis and indicators of immune infiltration, tumorigenicity, and metastasis.

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Section: Discussionmentioning

confidence: 99%

COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma

Liu,

Han,

Xuan

et al. 2024

Aging

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“…CSN6 gene copy number is positively correlated with tumor size 90 . Correspondingly, high CSN6 expression is significantly correlated with TNM stage, depth of invasion-pT status and lymph node metastasis-pN status in gastric cancer, breast cancer, and pancreatic adenocarcinoma 80,84,86 . Kaplan-Meier analysis has indicated that higher CSN6 expression is associated with shorter overall survival in patients with pancreatic cancer, HCC, or CRC 82,83,85 .…”

Section: Csn6 Overexpression In Cancermentioning

confidence: 93%

“…CSN6 is overexpressed in many types of cancer, according to analysis of human cancer patient data sets from Gene Expression Omnibus and Oncomine 79 . Furthermore, studies increasingly demonstrate that CSN6 expression is enhanced in various human cancers, including breast cancer 80,81 , HCC 82 , CRC 83 , gastric cancer 84 , pancreatic cancer 85,86 , melanoma 87 , glioblastoma 88 , and oral squamous cell carcinoma 89 . These studies have indicated that CSN6 is associated with the occurrence and development of carcinogenesis.…”

Section: Csn6 Overexpression In Cancermentioning

confidence: 99%

“…CSN6 promotes Skp2-mediated degradation of the cyclin-dependent kinase inhibitor p57 131 , whereas Jab1/CSN5 promotes p57 degradation independently of Skp2 in HCC 61 . In addition to the ubiquitin-dependent degradation of proteins, Jab1/CSN5 and CSN6 promote tumorigenesis via ubiquitin independent proteasomal degradation of the cell cycle regulators p16 INK4a and p14ARF 57,84 .…”

Section: Cell Cyclementioning

confidence: 99%

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Targeting the COP9 signalosome for cancer therapy

Zhang

Muhammad

et al. 2022

Cancer Biol Med

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The COP9 signalosome (CSN) is a highly conserved protein complex composed of 8 subunits (CSN1 to CSN8). The individual subunits of the CSN play essential roles in cell proliferation, tumorigenesis, cell cycle regulation, DNA damage repair, angiogenesis, and microenvironmental homeostasis. The CSN complex has an intrinsic metalloprotease that removes the ubiquitin-like activator NEDD8 from cullin-RING ligases (CRLs). Binding of neddylated CRLs to CSN is sensed by CSN4 and communicated to CSN5 with the assistance of CSN6, thus leading to the activation of deneddylase. Therefore, CSN is a crucial regulator at the intersection between neddylation and ubiquitination in cancer progression. Here, we summarize current understanding of the roles of individual CSN subunits in cancer progression. Furthermore, we explain how the CSN affects tumorigenesis through regulating transcription factors and the cell cycle. Finally, we discuss individual CSN subunits as potential therapeutic targets to provide new directions and strategies for cancer therapy.

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“…p16 , a cyclin-dependent kinase inhibitor, arrests cells in the G1 phase. Numerous carcinogens, including miR-30 and constitutive photomorphogenesis 9 signalosome 6, cause cancer by suppressing p16 expression, enhancing cell division, and interfering with efficient cellular senescence [ 197 , 198 ]. Liu et al also demonstrated that ablation of p16 in B cells could reverse aging while significantly increasing the incidence of B-cell neoplasms [ 199 ].…”

Section: The Deepest Connection: Genetics Of Aging and Cancersmentioning

confidence: 99%

Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions

Shen¹,

He²,

Hou³

et al. 2022

Aging and disease

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Recently, there has been an increase in the incidence of malignant tumors among the older population. Moreover, there is an association between aging and cancer. During the process of senescence, the human body suffers from a series of imbalances, which have been shown to further accelerate aging, trigger tumorigenesis, and facilitate cancer progression. Therefore, exploring the junctions of aging and cancer and searching for novel methods to restore the junctions is of great importance to intervene against aging-related cancers. In this review, we have identified the underlying pathogenetic mechanisms of aging-related cancers by comparing alterations in the human body caused by aging and the factors that trigger cancers. We found that the common mechanisms of aging and cancer include cellular senescence, alterations in proteostasis, microbiota disorders (decreased probiotics and increased pernicious bacteria), persistent chronic inflammation, extensive immunosenescence, inordinate energy metabolism, altered material metabolism, endocrine disorders, altered genetic expression, and epigenetic modification. Furthermore, we have proposed that aging and cancer have common means of intervention, including novel uses of common medicine (metformin, resveratrol, and rapamycin), dietary restriction, and artificial microbiota intervention or selectively replenishing scarce metabolites. In addition, we have summarized the research progress of each intervention and revealed their bidirectional effects on cancer progression to compare their reliability and feasibility. Therefore, the study findings provide vital information for advanced research studies on age-related cancers. However, there is a need for further optimization of the described methods and more suitable methods for complicated clinical practices. In conclusion, targeting aging may have potential therapeutic effects on aging-related cancers.

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

Cited by 13 publications

References 49 publications

COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma

COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma

Targeting the COP9 signalosome for cancer therapy

Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions

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