Increased genetic instability and accelerated progression of colitis-associated colorectal cancer through intestinal epithelium–specific deletion of Klf4

Kruppel-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 (Klf4 ^DIS ) and control mice (Klf4 ^fl / ^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 Klf4 ^fl / ^fl mice during tumor development. Klf4 ^DIS mice treated with AOM/DSS developed significantly more adenomatous polyps and carcinomas in situ in comparison with treated Klf4 ^fl / ^fl mice. Adenomatous polyps, but not normal-appearing mucosa, from colonic tissues of treated Klf4 ^DIS 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.