Increased Genetic Instability and Accelerated Progression of Colitis-Associated Colorectal Cancer through Intestinal Epithelium–specific Deletion of<i>Klf4</i>

Abstract

Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, regulates homeostasis of the intestinal epithelium. Previously, it was reported that KLF4 functions as a tumor suppressor in colorectal cancer. Here, evidence demonstrates that KLF4 mitigates the development and progression of colitis-associated colorectal cancer (CAC) in a murine model. Mice with intestinal epithelium-specific deletion of <i>Klf4</i> (<i>Klf4^ΔIS</i> ) and control mice (<i>Klf4^fl/fl</i> ) were used to explore the role of KLF4 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. Upon AOM and DSS treatment, KLF4 expression was progressively lost in colonic tissues of <i>Klf4^fl/fl</i> mice during tumor development. <i>Klf4^ΔIS</i> mice treated with AOM/DSS developed significantly more adenomatous polyps and carcinomas <i>in situ</i> in comparison with treated <i>Klf4^fl/fl</i> mice. Adenomatous polyps, but not normal-appearing mucosa, from colonic tissues of treated <i>Klf4^ΔIS</i> mice contained a significantly increased number of mitotic cells with more than 2 centrosomes relative to treated control mice. KLF4 and p53 colocalize to the centrosomes in mouse embryonic fibroblasts (MEF). Absence of KLF4 in <i>Klf4^-/-</i> MEFs inhibits and its overexpression restores p53 localization to the centrosomes in <i>Klf4^-/-</i> MEFs. IMPLICATIONS: Taken together, these results indicate that KLF4 plays a protective role against progression of CAC by guarding against genetic instability.