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Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7

Author

Listed:
  • 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
    National Center for Protein Sciences (The PHOENIX Center, Beijing)
    State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University)

  • 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
    National Center for Protein Sciences (The PHOENIX Center, Beijing)
    State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University)

  • Sheng Ye

    (Zhejiang University)

  • Fangfang Zhou

    (Soochow University)

  • Long Zhang

    (Zhejiang University)

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.

Suggested Citation

  • 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 & J, 2017. "Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02029-7
    DOI: 10.1038/s41467-017-02029-7
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    Cited by:

    1. Alexander Vdovin & Tomas Jelinek & David Zihala & Tereza Sevcikova & Michal Durech & Hana Sahinbegovic & Renata Snaurova & Dhwani Radhakrishnan & Marcello Turi & Zuzana Chyra & Tereza Popkova & Ondrej, 2022. "The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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