Increased Genetic Instability and Accelerated Progression of Colitis-Associated Colorectal Cancer through Intestinal Epithelium–specific Deletion ofKlf4

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 Klf4 (Klf4ΔIS) and control mice (Klf4fl/fl) 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 Klf4fl/fl mice during tumor development. Klf4ΔIS mice treated with AOM/DSS developed significantly more adenomatous polyps and carcinomas in situ in comparison with treated Klf4fl/fl mice. Adenomatous polyps, but not normal-appearing mucosa, from colonic tissues of treated Klf4ΔIS 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 Klf4−/− MEFs inhibits and its overexpression restores p53 localization to the centrosomes in Klf4−/− MEFs. Implications: Taken together, these results indicate that KLF4 plays a protective role against progression of CAC by guarding against genetic instability.