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Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development

Author

Listed:
  • Baojun Chang

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Kandice L. Tessneer

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • John McManus

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Xiaolei Liu

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
    University of Oklahoma Health Sciences Center)

  • Scott Hahn

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Satish Pasula

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Hao Wu

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Hoogeun Song

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Yiyuan Chen

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Xiaofeng Cai

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Yunzhou Dong

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Megan L. Brophy

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
    University of Oklahoma Health Sciences Center)

  • Ruby Rahman

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation)

  • Jian-Xing Ma

    (Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center)

  • Lijun Xia

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
    University of Oklahoma Health Sciences Center)

  • Hong Chen

    (Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
    University of Oklahoma Health Sciences Center)

Abstract

Uncontrolled canonical Wnt signalling supports colon epithelial tumour expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, the involvement of epsins in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signalling effector, dishevelled (Dvl2), and impairing Wnt signalling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signalling in colon cancer cells to ensure robust colon cancer progression. The pro-carcinogenic role of Epsins suggests that they are potential therapeutic targets to combat colon cancer.

Suggested Citation

  • Baojun Chang & Kandice L. Tessneer & John McManus & Xiaolei Liu & Scott Hahn & Satish Pasula & Hao Wu & Hoogeun Song & Yiyuan Chen & Xiaofeng Cai & Yunzhou Dong & Megan L. Brophy & Ruby Rahman & Jian-, 2015. "Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development," Nature Communications, Nature, vol. 6(1), pages 1-17, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7380
    DOI: 10.1038/ncomms7380
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