Intestinal knockout of Nedd4 enhances growth of Apcmin tumors.

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.