Haploinsufficiency of Krüppel-Like Factor 5 Rescues the Tumor-Initiating Effect of the Apc^Min Mutation in the Intestine

¹Division of Digestive Diseases, Department of Medicine, ²Department of Pharmacology, and ³Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

^* To whom correspondence should be addressed. E-mail: vyang{at}emory.edu.

	Abstract

Inactivation of the tumor suppressor adenomatous polyposis coli, with the resultant activation of -catenin, is the initiating event in the development of a majority of colorectal cancers. Krüppel-like factor 5 (KLF5), a proproliferative transcription factor, is highly expressed in the proliferating intestinal crypt epithelial cells. To determine whether KLF5 contributes to intestinal adenoma formation, we examined tumor burdens in Apc^Min/+ mice and Apc^Min/+/Klf5^+/- mice. Compared with Apc^Min/+ mice, Apc^Min/+/Klf5^+/- mice had a 96% reduction in the number of intestinal adenomas. Reduced tumorigenicity in the Apc^Min/+/Klf5^+/- mice correlated with reduced levels and nuclear localization of -catenin as well as reduced expression of two -catenin targets, cyclin D1 and c-Myc. In vitro studies revealed a physical interaction between KLF5 and -catenin that enhanced the nuclear localization and transcriptional activity of -catenin. Thus, KLF5 is necessary for the tumor-initiating activity of -catenin during intestinal adenoma formation in Apc^Min/+ mice, and reduced expression of KLF5 offsets the tumor-initiating activity of the Apc^Min mutation by reducing the nuclear localization and activity of -catenin. [Cancer Res 2009;69(10):4125–33]

Key Words: KLF5, APC, adenomas, colorectal cancer, -catenin