Haploinsufficiency of Krüppel-Like Factor 5 Rescues the Tumor-Initiating Effect of the ApcMin Mutation in the Intestine

• Authors: Beth B. McConnell, Emory University; Agnieszka B. Bialkowska, Emory University; Mandayam O. Nandan, Emory University; Amr M. Ghaleb, Emory University; Frank J Gordon, Emory University; Vincent W. Yang, Emory University
• Journal Title: Cancer Research
• Volume: Volume 69, Number 10
• Publisher: American Association for Cancer Research | 2009-05-15, Pages 4125-4133
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/0008-5472.CAN-08-4402
• Subjects: Health Sciences, Oncology

Abstract

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 ApcMin/+ mice and ApcMin/+/Klf5+/− mice. Compared with ApcMin/+ mice, ApcMin/+/Klf5+/− mice had a 96% reduction in the number of intestinal adenomas. Reduced tumorigenicity in the ApcMin/+/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 ApcMin/+ mice, and reduced expression of KLF5 offsets the tumor-initiating activity of the ApcMin mutation by reducing the nuclear localization and activity of β-catenin.