Tumor and Stem Cell Biology KLF5 Regulates the Integrity and Oncogenicity of Intestinal Stem Cells

The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5þ crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical tomaintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in themouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. Inmice, inducible deletion of Klf5 in Lgr5þ stem cells suppressed their proliferation and survival in amanner associatedwith nuclear localization ofb-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of b-catenin in Lgr5þ stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/b-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer. Cancer Res; 74(10);