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Nat Commun. 2017 Dec 13;8(1):2116. doi: 10.1038/s41467-017-02029-7.

Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7.

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Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
Institutes of Biology and Medical Science, Soochow University, 215123, Suzhou, China.
State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 310000, Hangzhou, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, 100039, Beijing, China.
National Center for Protein Sciences (The PHOENIX Center, Beijing), 102206, Beijing, China.
State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, 200433, Shanghai, China.
Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94158, USA.
Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands.
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
Tsinghua University, 100084, Beijing, China.
Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, 310058, Zhejiang, China.


Metastasis is the main cause of death in cancer patients. TGF-β is pro-metastatic for malignant cancer cells. Here we report a loss-of-function screen in mice with metastasis as readout and identify OTUD1 as a metastasis-repressing factor. OTUD1-silenced cancer cells show mesenchymal and stem-cell-like characteristics. Further investigation reveals that OTUD1 directly deubiquitinates the TGF-β pathway inhibitor SMAD7 and prevents its degradation. Moreover, OTUD1 cleaves Lysine 33-linked poly-ubiquitin chains of SMAD7 Lysine 220, which exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface. Importantly, OTUD1 is lost in multiple types of human cancers and loss of OTUD1 increases metastasis in intracardial xenograft and orthotopic transplantation models, and correlates with poor prognosis among breast cancer patients. High levels of OTUD1 inhibit cancer stemness and shut off metastasis. Thus, OTUD1 represses breast cancer metastasis by mitigating TGF-β-induced pro-oncogenic responses via deubiquitination of SMAD7.

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