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Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation

Author

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  • Yadi Wu

    (The University of Kentucky, College of Medicine
    Markey Cancer Center, The University of Kentucky, College of Medicine)

  • Yu Wang

    (The University of Kentucky, College of Medicine
    Markey Cancer Center, The University of Kentucky, College of Medicine)

  • Yiwei Lin

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Yajuan Liu

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Yifan Wang

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Jianhang Jia

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Puja Singh

    (The Hormel Institute, University of Minnesota)

  • Young-In Chi

    (The Hormel Institute, University of Minnesota)

  • Chi Wang

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Chenfang Dong

    (Zhejiang University School of Medicine)

  • Wei Li

    (The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University)

  • Min Tao

    (The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University)

  • Dana Napier

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Qiuying Shi

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine)

  • Jiong Deng

    (Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine)

  • B Mark Evers

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    the University of Kentucky, College of Medicine)

  • Binhua P. Zhou

    (Markey Cancer Center, The University of Kentucky, College of Medicine
    The University of Kentucky, College of Medicine
    State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine)

Abstract

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitro and in vivo. Our study reveals a critical Dub3–Snail1 signalling axis in EMT and metastasis, and provides an effective therapeutic approach against breast cancer.

Suggested Citation

  • Yadi Wu & Yu Wang & Yiwei Lin & Yajuan Liu & Yifan Wang & Jianhang Jia & Puja Singh & Young-In Chi & Chi Wang & Chenfang Dong & Wei Li & Min Tao & Dana Napier & Qiuying Shi & Jiong Deng & B Mark Evers, 2017. "Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation," Nature Communications, Nature, vol. 8(1), pages 1-16, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14228
    DOI: 10.1038/ncomms14228
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