Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7

Zhengkui Zhang, Yao Fan, Feng Xie, Hang Zhou, Ke Jin, Li Shao, Wenhao Shi, Pengfei Fang, Bing Yang, Hans van Dam, Peter ten Dijke, Xiaofeng Zheng, Xiaohua Yan, Junling Jia, Min Zheng, Jin Jin, Chen Ding, Sheng Ye, Fangfang Zhou and Long Zhang ()
Additional contact information
Zhengkui Zhang: Zhejiang University
Yao Fan: Zhejiang University
Feng Xie: Soochow University
Hang Zhou: Zhejiang University
Ke Jin: Zhejiang University
Li Shao: The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease
Wenhao Shi: Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Pengfei Fang: Zhejiang University
Bing Yang: University of California San Francisco, San Francisco
Hans van Dam: Leiden University Medical Center, Postbus 9600
Peter ten Dijke: Leiden University Medical Center, Postbus 9600
Xiaofeng Zheng: Metastasis Research Center, University of Texas MD Anderson Cancer Center
Xiaohua Yan: Tsinghua University
Junling Jia: Zhejiang University
Min Zheng: The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease
Jin Jin: Zhejiang University
Chen Ding: Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Sheng Ye: Zhejiang University
Fangfang Zhou: Soochow University
Long Zhang: Zhejiang University

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-02029-7

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