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; Hong Chen

doi:10.1038/ncomms7380

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, Hong Chen^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English (US)
Article number	6380
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7380
State	Published - Mar 16 2015

Funding

We thank Dr Kirk Bergstrom in Dr Lijun Xia’s laboratory in our department and Dr Bruce Vallance at the University of British Columbia in Canada, for sharing the CMT-93 cell line. We also thank the Oklahoma Medical Research Foundation imaging core for help with the histological studies. This work was supported in part by NIH grants R01HL-093242, R01HL-118676, P20 RR018758, a National Scientific Development Grant from the American Heart Association (AHA; 0835544N), grant from the Oklahoma Center for Advanced Science and Technology (OCAST) HR09-116 and a grant from the Department of Defense W81XWH-11-1-00226 to H.C.; NIH grants R01DK085691 and P01HL-085607 to L.X.; grants from OCAST AR11-043 and AH14-056 and from AHA-SDG 12SDG8760002 to Y.D.; AHA Postdoctoral fellowships 13POST16940008 to K.L.T. and 13POST17270006 to S.P.; AHA Predoctoral fellowship RSRCH016952 to X.L.

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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10.1038/ncomms7380

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title = "Epsin is required for dishevelled stability and Wnt signalling activation in colon cancer development",

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.",

author = "Baojun Chang and Tessneer, {Kandice L.} and John McManus and Xiaolei Liu and Scott Hahn and Satish Pasula and Hao Wu and Hoogeun Song and Yiyuan Chen and Xiaofeng Cai and Yunzhou Dong and Brophy, {Megan L.} and Ruby Rahman and Ma, {Jian Xing} and Lijun Xia and Hong Chen",

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doi = "10.1038/ncomms7380",

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AU - Tessneer, Kandice L.

AU - McManus, John

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AU - Hahn, Scott

AU - Pasula, Satish

AU - Wu, Hao

AU - Song, Hoogeun

AU - Chen, Yiyuan

AU - Cai, Xiaofeng

AU - Dong, Yunzhou

AU - Brophy, Megan L.

AU - Rahman, Ruby

AU - Ma, Jian Xing

AU - Xia, Lijun

AU - Chen, Hong

PY - 2015/3/16

Y1 - 2015/3/16

N2 - 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.

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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