Intestinal Tumor Progression Is Associated with Altered Function of KLF5

Krüppel-like transcription factors have been linked to cell growth regulation and tumorigenesis in a number of systems. In the intestinal epithelium, expression of KLF5 (IKLF/BTEB2) is limited to proliferating crypt cells, indicating a growth-promoting role. Consistent with this role, we demonstrate that expression of KLF5 in non-transformed intestinal epithelial cells (ileal IEC-18 and Immorto-Min Colon Epithelial (IMCE) cells) enhances colony formation, cyclin D1 transcription, and cell growth. However, in contrast to these effects in non-transformed cells, KLF5 reduced colony number, failed to enhance cyclin Dl transcription, and was negatively correlated with cell growth in colon cancer cell lines. The relationship between tumor progression and KLF5 was further investigated using Ras-mediated transformation of IEC-18 and IMCE cells as syngeneic models. Ras-transformation recapitulated differences in the effects of KLF5 on cell growth and cyclin D1 transcription, providing a direct link between intestinal tumor progression and altered function of KLF5. Ras-transformation also markedly down-regulated KLF5; further analysis indicated that reduced expression of KLF5 mRNA and destabilization of KLF5 protein occur in intestinal tumors. Reduced levels of KLF5 mRNA were also detected in APC^min mouse and human familial adenomatous polyposis adenomas compared with normal crypt epithelium, indicating that down-regulation of KLF5 is an early event in intestinal tumorigenesis in vivo. Collectively, these data indicate that intestinal tumor progression is associated with a change in the growth-related functions of KLF5 and that intestinal tumors down-regulate KLF5 expression by multiple mechanisms.