CSN6 expression is associated with pancreatic cancer progression and predicts poor prognosis

Hou

et al. 2021

Cell Death Dis

As a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression, but its biological functions and molecular mechanisms in melanoma remain unknown. Our study showed that CSN6 expression was upregulated in melanoma patients and cells, and correlated with poor survival in melanoma patients. In melanoma cells, CSN6 knockdown remarkably inhibited cell proliferation, tumorigenicity, migration, and invasion, whereas CSN6 recovery rescued the proliferative and metastatic abilities. Notably, we identified that CSN6 stabilized CDK9 expression by reducing CDK9 ubiquitination levels, thereby activating CDK9-mediated signaling pathways. In addition, our study described a novel CSN6-interacting E3 ligase UBR5, which was negatively regulated by CSN6 and could regulate the ubiquitination and degradation of CDK9 in melanoma cells. Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5/CDK9 pathway to promote melanoma cell proliferation and metastasis. Thus, this study illustrates the mechanism by which the CSN6-UBR5-CDK9 axis promotes melanoma development, and demonstrate that CSN6 may be a potential biomarker and anticancer target in melanoma.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9

Hou

et al. 2021

Cell Death Dis

“…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%

“…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 . In addition, CSN6 gene mRNA levels, assessed from TCGA data, have revealed higher CSN6 expression in tumor tissue than in normal tissue, and indicated that amplification of the CSN6 gene is associated with advanced disease stage 83 .…”

Section: Csn6 Overexpression In Cancermentioning

confidence: 99%

Targeting the COP9 signalosome for cancer therapy

Muhammad

et al. 2022

Cancer Biol Med

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.

“…CSN subunits have a conserved structure; for example, the Mpr1-Pad1-N-terminal (MPN) domain in CSN5 contains a metalloproteinase motif, which has catalytic activity and is involved in the regulation of protein demethylation ( 16 – 18 ). MPN in CSN6 may serve as a structural scaffold or play a regulatory function ( 16 , 19 , 20 ). Previous studies have confirmed that CSN inhibits the ubiquitin-dependent degradation of numerous tumor-related proteins ( 21 – 23 ), such as P27, P53, E3 ubiquitin-protein ligase Mdm2, Smad7, Runt-related transcription factor 3, DNA-binding protein inhibitor ID-1, S-phase kinase-associated protein 2 and hypoxia-inducible factor 1 ( 14 ), indicating that CSN plays an important role in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

CSN1 facilitates proliferation and migration of hepatocellular carcinoma cells by upregulating cyclin A2 expression

Yin

et al. 2020

Mol Med Rep

Constitutive photomorphogenesis 9 signalosome subunit 1 (CSN1) plays an important role in the ubiquitin-proteasome pathway and regulates various cellular processes, such as the cell cycle and DNA repair. The CSN complex consists of eight subunits (CSN1 to CSN8) and regulates the tumorigenesis of a variety of tumor types. However, the exact role of CSN1 in hepatocellular carcinoma (HCC) remains unclear. The present study evaluated the expression and biological effects of CSN1 in HCC tissue samples and cell lines. CSN1 was significantly overexpressed in HCC tissue and cell lines, compared with their normal counterparts. In patients with HCC, elevated CSN1 levels correlated with tumor size, tumor metastasis and tumor stage. Loss-of-function assays indicated that CSN1 knockdown inhibited the proliferation and migration HCC cells. In addition, CSN1 promoted the expression of cyclin A2 in a ubiquitination-independent manner. Lastly, xenograft experiments indicated that CSN1 promoted HCC tumor growth in vivo . The present study suggested that CSN1 inhibition could represent a potential approach for the prevention of HCC progression and metastasis.