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

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-Xing Ma, Lijun Xia and Hong Chen ()
Additional contact information
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
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
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
Hong Chen: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7380

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