The Myc 3′ Wnt-Responsive Element Suppresses Colonic Tumorigenesis

Abstract

Mutations in components of the Wnt/β-catenin signaling pathway are commonly found in colorectal cancers, and these mutations cause aberrant expression of genes controlled by Wnt-responsive DNA elements (WREs). While the c-Myc proto-oncogene (Myc) is required for intestinal phenotypes associated with pathogenic Wnt/β-catenin signaling in vivo, the WREs that control Myc expression in this setting have yet to be fully described. Previously, we demonstrated that the Myc 3′ WRE was required for intestinal homeostasis and intestinal repair in response to damage. Here, we tested the role of the Myc 3′ WRE in intestinal tumorigenesis using two independent mouse models. In comparison to Apc^Min/+ mice, Apc^Min/+ Myc 3′ WRE^−/− mice contained 25% fewer tumors in the small intestine. Deletion of the Myc 3′ WRE^−/− in the Apc^Min/+ background resulted in 4-fold more colonic tumors. In a model of colitis-associated colorectal cancer, the Myc 3′ WRE suppressed colonic tumorigenesis, most notably within the cecum. Using chromatin immunoprecipitation and transcript analysis of purified colonic crypts, we found that the Myc 3′ WRE is required for the transcriptional regulation of Myc expression in vivo. These results emphasize the critical role of the Myc 3′ WRE in maintaining homeostatic Myc expression.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00969-13.

ACKNOWLEDGMENTS

We thank members of the Yochum laboratory for helpful discussions and Kang Li in the Morphological and Molecular Pathology Core Research Laboratory (Penn State University College of Medicine) for his help with embedding tissue sections and preparing slides for immunohistochemistry.

This research was supported by National Institutes of Health grant R01DK080805 (G.S.Y.).