Deubiquitinase USP29 promotes gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein

Snail is a master inducer of epithelial-mesenchymal transition (EMT) and metastasis, however, Snail protein is labile and is quickly degraded through the predominate ubiquitination-mediated proteasome pathway. Deubiquitinases (DUBs) can counteract the Snail degradation process to maintain high level...

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Bibliographic Details
Published in:Oncogene 2020-10, Vol.39 (44), p.6802-6815
Main Authors: Qian, Wenli, Li, Qi, Wu, Xinglong, Li, Wenguo, Li, Qiwei, Zhang, Jie, Li, Mengying, Zhang, Dan, Zhao, Hongxia, Zou, Xiuqun, Jia, Hao, Zhang, Lingqiang, Yang, Xiao-Dong, Hou, Zhaoyuan
Format: Article
Language:English
Subjects:
Cell adhesion & migration
Cell Line, Tumor
Cell migration
Cell Movement - genetics
Datasets as Topic
Degradation
Dephosphorylation
Development and progression
Ectopic expression
Epithelial-Mesenchymal Transition - genetics
Gastric cancer
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic aspects
Health aspects
HEK293 Cells
Humans
Hypoxia
Kaplan-Meier Estimate
Medical prognosis
Mesenchyme
Metastases
Metastasis
Phosphatases
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Prognosis
Proteases
Proteasomes
Protein Binding
Protein Stability
Proteins
Proteolysis
Snail Family Transcription Factors - metabolism
Snail protein
Stomach cancer
Stomach Neoplasms - genetics
Stomach Neoplasms - mortality
Stomach Neoplasms - pathology
Tumor necrosis factor-α
Ubiquitin
Ubiquitin-Specific Proteases - genetics
Ubiquitin-Specific Proteases - metabolism
Ubiquitination
Zinc finger proteins
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Summary:Snail is a master inducer of epithelial-mesenchymal transition (EMT) and metastasis, however, Snail protein is labile and is quickly degraded through the predominate ubiquitination-mediated proteasome pathway. Deubiquitinases (DUBs) can counteract the Snail degradation process to maintain high level of Snail protein in cancer cells. In this study, we screened a cDNA library containing 79 DUBs, and discovered that a panel of DUBs consisting of USP13, USP28, USP29, USP37, OTUD6A, and DUB3 can markedly stabilize Snail protein, with USP29 displaying the strongest activity to prevent Snail degradation. Mechanistically, USP29 enhances the interaction of Snail and SCP1, resulting in simultaneous dephosphorylation and deubiquitination of Snail and thereafter cooperative prevention of Snail degradation. Biologically, ectopic expression of USP29 promotes gastric cancer cell migration, and depletion of Snail abolishes USP29-mediated cell migration; and USP29 can be induced by major EMT and metastatic inducing factors such as TGFβ, TNFα, and hypoxia. More importantly, high expression levels of Snail, USP29, and SCP1 are associated with poor survival and prognosis. Collectively, these data indicate that Snail is a crucial substrate for USP29 to promote cell migration and USP29/SCP1 complex may be new therapeutic targets to treat metastatic cancer.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-020-01471-0