Haploinsufficiency of Krüppel-like factor 5 rescues the tumor-initiating effect of the Apc^Min mutation in the intestine

Inactivation of the tumor suppressor adenomatous polyposis coli, with the resultant activation of β-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 β-catenin as well as reduced expression of two β-catenin targets, cyclin D1 and c-Myc. In vitro studies revealed a physical interaction between KLF5 and β-catenin that enhanced the nuclear localization and transcriptional activity of β-catenin. Thus, KLF5 is necessary for the tumor-initiating activity of β-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 β-catenin.