Clinical Implications of CSN6 Protein Expression and Correlation with Mutant-type P53 Protein in Breast Cancer

Wang, Wenqian; Tang, Miao; Zhang, Lei; Xu, Xiaoyin; Qi, Xinyang; Yang, Yang; Jin, Feng; Chen, Bo

doi:10.1093/jjco/hyt148

Cited by 13 publications

(13 citation statements)

References 15 publications

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“…However, some tumors adapt to DNA damage-inducing chemotherapeutic drugs, such as cisplatin, by enhancing DDR activity, precipitating the need for DDR inhibitors [ 187 ]. In some human cancers, elevated expression levels of CSN5 and CSN6 are correlated with cancer progression and poor prognosis [ 148 , 188 , 189 , 190 , 191 ], which may be due to increased DDR function reducing the efficacy of cytotoxic therapies employing DNA damaging agents. Given that both the CSN and neddylation appear to have a significant regulatory function in the DDR, we predict that the CSN will be an increasingly attractive drug target for the development of chemotherapy and radiosensitization agents to treat cancer.…”

Section: Discussionmentioning

confidence: 99%

The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair

Chung

Dellaire

2015

Biomolecules

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The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA. Post-translational modifications by ubiquitin and ubiquitin-like proteins, such as SUMO and NEDD8, have roles in coordinating the progression of DDR. Proteins in the neddylation pathway have also been linked to regulating DDR. Of interest is the COP9 signalosome (CSN), a multi-subunit metalloprotease present in eukaryotes that removes NEDD8 from cullins and regulates the activity of cullin-RING ubiquitin ligases (CRLs). This in turn regulates the stability and turnover of a host of CRL-targeted proteins, some of which have established roles in DDR. This review will summarize the current knowledge on the role of the CSN and neddylation in DNA repair.

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Section: Discussionmentioning

confidence: 99%

The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair

Chung

Dellaire

2015

Biomolecules

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“…However, we do not know whether LKB1 is active in cervical carcinomas that express it. For some tumor suppressor genes, such as p53, proteins can be expressed in tissues with mutations [30]. …”

Section: Discussionmentioning

confidence: 99%

Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells

Zhang

Wang

Zhao

et al. 2014

Gynecologic Oncology

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Objectives To characterize the biological activities of LKB1, examine LKB1 protein expression and identify LKB1-regulated genes that may serve as therapeutic targets in cervical cancer. Methods Proliferation of cervical cancer HeLa cells expressing LKB1 was examined. LKB1 expression in normal cervical tissues and cervical cancers was assessed by immunohistochemistry. Gene expression profiles of cervical cancer HeLa cells stably expressing LKB1 were analyzed by microarray. Differentially expressed genes were analyzed using Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) PATHWAY database. Quantitative RT-PCR was used to validate the microarray data. The expression of lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) was confirmed by western blotting. Results Expression of LKB1 inhibited HeLa cell proliferation and activated AMPK and was lost in more than 50% of cervical carcinomas. More than 200 genes were differentially expressed between HeLa cells with and without LKB1. Bioinformatics analysis with GO annotation indicated that LKB1 plays a role in receiving diverse stimuli and converting them into molecular signals. KEGG PATHWAY analysis showed that 8 pathways were significantly regulated. These include arginine and proline metabolism and inositol phosphate metabolism. The differential expression of 7 randomly selected genes was confirmed by quantitative RT-PCR. Furthermore, the steady-state level of INPP4B protein was up-regulated in LKB1-overexpressing cells. Conclusions This study establishes LKB1 as an important tumor suppressor in cervical cancer and sheds light on a novel signaling pathway regulated by LKB1.

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“…Furthermore, CSN6 can also coordinate with E3 ligase to mediate ubiquitination and degradation of cancer associated proteins [14]. Previous studies have identified that CSN6 was implicated in tumor progression, because it is overexpressed in multiple common types of cancers, such as cervical cancer, thyroid cancer, colorectal cancer, breast cancer, lung cancer, hepatocellular carcinoma and glioblastoma [15][16][17][18][19]. In particular, the expression profiles of CSN6 in human cancer patient database from Gene Expression Omnibus and Oncomine illustrate that CSN6 is overexpressed in >50% of cases of glioblastoma, pancreatic cancer and breast cancer [20].…”

Section: Ivyspringmentioning

confidence: 99%

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

et al. 2020

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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.

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Clinical Implications of CSN6 Protein Expression and Correlation with Mutant-type P53 Protein in Breast Cancer

Abstract: Constitutive photomorphogenesis 9 subunit 6 might be a new potential biomarker for breast cancer. However, the underlying mechanisms of constitutive photomorphogenesis 9 subunit 6's involvement are still unclear.

Cited by 13 publications

References 15 publications

The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair

The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair

Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells

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

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