CSN6 promotes the cell migration of breast cancer cells by positively regulating Snail1 stability

Abstract

Background: CSN6, a subunit of the highly conserved constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has been reported to be implicated in tumor progression in various kinds of malignant tumors. However, the mechanism underlying CSN6 in the tumor development of breast cancer has not yet been fully elucidated. Methods: CSN6 staining in breast cancer tissues and paracancerous tissues was measured by tissue microarray (TMA) technology. The metastatic effect of CSN6 was measured by cell migration assay. Co-immunoprecipitation study was used to show the interaction between the protein CSN6 and Snail1. Ubiquitination assay was performed to validate whether ubiquitination is involved in the upregulation of Snail1 by CSN6. The impact of CSN6 on tumor metastasis in vivo was analyzed using xenotransplantation experiments in BALB/c mice. Results: Here, we demonstrated that CSN6 expression was dramatically increased in breast cancer tissues compared with paired adjacent cancerous tissues. CSN6 promoted the cell migration and wound healing abilities in breast cancer cell lines. Also we showed that CSN6 associates with Snail1 and enhances Snail1 protein level by inhibiting the ubiquitin-mediated degradation of Snail1. Thus, CSN6 is involved in positively regulating the stability of Snail1. We further proved that CSN6 protein level was positively correlated with the Snail1 expression in xenograft model. Conclusion: These findings provide new insight into applicability of using the CSN6-Snail1 axis as a potential therapeutic target in breast cancer.

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

“…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 ].…”

“…Carvalho and colleagues identified COPS2 as a possible candidate target gene for miR-15a-3p to inhibit the progression of colorectal adenoma [ 56 ]. Alternatively, COPS3 may promote clear cell renal cell carcinoma progression by regulating phospho-AKT (Thr308), Cyclin D1, and Caspase-3 expression [ 57 ], while COPS5, -6, and -8 overexpression enhanced cellular proliferation [ 23 , 45 , 46 , 58 , 59 ], EMT [ 42 , 55 , 60 , 61 ], and vascular invasion [ 62 ]. Zheng and colleagues also found that KRT19P3 suppressed gastric tumor growth and metastasis through a COPS7A-regulated NF-κB pathway, suggesting that COPS7A acts as a suppressor of gastric cancer [ 63 ].…”

Targeting the COP9 signalosome for cancer therapy

“…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 .…”

“…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.…”

“…For instance, NF-κB is required for the induction of CSN2, which in turn inhibits the ubiquitination and degradation of the transcription factor Snail 39 . Other subunits, such as CSN6, also attenuate transcription factor expression through ubiquitination in cancer cells 79,80,86 . However, the regulatory mechanisms of the CSN complex and its individual subunits in regulating gene expression remain to be further investigated.…”