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Intestinal knockout of Nedd4 enhances growth of Apcmin tumors

Oncogene volume 35, pages 5839–5849 (2016)Cite this article

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Abstract

Nedd4 (Nedd4-1) is an E3 ubiquitin ligase that belongs to the HECT family and comprises a C2-WW(n)-HECT domain architecture. Although it has been reported to regulate growth factor receptors and cellular signaling, its role in cancer development has been controversial, with some studies proposing that it promotes cancer while others suggest it inhibits tumor growth. Here, we tested the effect of Nedd4 on intestinal tumor formation and growth using Nedd4-knockout mice (Nedd4 floxed (fl) mice crossed to villin-Cre mice). Although we find that knockout of Nedd4 on its own does not cause tumor growth, its knockout in the context of Apc+/min-derived colorectal tumors leads to augmentation of tumor growth, suggesting that Nedd4 normally suppresses intestinal WNT signaling and growth of colonic tumors. WNT signaling microarray, immunoblotting and immunohistochemistry analyses of tumors derived from the Villin-Cre;Nedd4fl/fl;Apc+/min colons demonstrated elevated expression of the WNT upstream effectors LEF1 (full length) and YY1 in these tumors relative to control (Apc+/min alone) tumors. Together, these results suggest that Nedd4 suppresses colonic WNT signaling and tumor growth, at least in part, by suppressing the transcription factors LEF1 and YY1.

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Acknowledgements

We would like to thank Kazuko Hay for technical support and Dr Sylvie Robine for the Vil-CreERT2 mice. This grant was supported by the Canadian Institute of Health Research (MOP-130422, to DR), the German Research Foundation SPP1365/KA3423/1-1 (to HK) and the Fritz Thyssen Foundation (to HK). DR is a recipient of a Canada Research Chair form the Canadian Foundation for Innovation (CFI).

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Authors and Affiliations

  1. and Biochemistry Department, Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    C Lu, C Thoeni & D Rotin

  2. Mount Sinai Hospital, University Health Network, University of Toronto,, Toronto,, Ontario, Canada

    A Connor & S Gallinger

  3. Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Goettingen, Germany

    H Kawabe

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Correspondence to D Rotin.

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Lu, C., Thoeni, C., Connor, A. et al. Intestinal knockout of Nedd4 enhances growth of Apcmin tumors. Oncogene 35, 5839–5849 (2016). https://doi.org/10.1038/onc.2016.125

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