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

Oncogene volume 39, pages 6802–6815 (2020)Cite this article

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Abstract

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.

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Fig. 1: USP29 increases Snail protein level and directly interacts with Snail protein.
Fig. 2: The PH and UCH domains of USP29 bind the zinc finger region of Snail.
Fig. 3: USP29 prevents Snail degradation.
Fig. 4: USP29 reduces ubiquitination level of Snail.
Fig. 5: USP29 promotes cell migration and invasion.
Fig. 6: TGFβ, TNFα, and hypoxia induce USP29 expression in gastric cancer cells.
Fig. 7: USP29 interacts with SCP1.
Fig. 8: USP29 and SCP1 cooperatively stabilize Snail protein.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China to ZH (81872131 and 31671415) and to XDY (31570770 and 31770818).

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  1. These authors contributed equally: Wenli Qian, Qi Li

Authors and Affiliations

  1. Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Wenli Qian, Qi Li, Jie Zhang, Mengying Li, Dan Zhang, Xiuqun Zou, Hao Jia & Zhaoyuan Hou

  2. State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Qi Li

  3. Central Clinical Laboratory, Lanling People’s Hospital, Lanling County, 277700, Shandong Province, China

    Xinglong Wu & Zhaoyuan Hou

  4. Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Minister of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Wenguo Li & Xiao-Dong Yang

  5. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Qiwei Li

  6. Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland

    Hongxia Zhao

  7. State Key Laboratory of Proteomics, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China

    Lingqiang Zhang

  8. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Zhaoyuan Hou

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Correspondence to Lingqiang Zhang, Xiao-Dong Yang or Zhaoyuan Hou.

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Qian, W., Li, Q., Wu, X. et al. Deubiquitinase USP29 promotes gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein. Oncogene 39, 6802–6815 (2020). https://doi.org/10.1038/s41388-020-01471-0

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