Abstract 2293: KLF5 is essential for oncogenesis of intestinal tumors and control of intestinal stem cells.

Abstract

Abstract Genetic changes in intestinal epithelial stem cells are more important for oncogenesis of intestinal tumors than such changes in non-stem cells. A large-scale sequencing analysis of human colorectal carcinoma (CRC) revealed that Wnt/β-catenin signal activation is the most frequent genomic changes (92-97%) in human colorectal carcinoma (CRC). However, fundamental significance of its signal activation of intestinal stem cells is still remains unsolved. Kruppel-like factor 5 (KLF5) is one of KLF zinc finger transcription factor with diverse biological functions. KLF5 has stronger expression in the bottom of intestinal crypts, where the stem cells reside, and weaker expression in villi as the epithelial cells differentiate into more mature cells, which is complementary pattern of KLF4. KLF5 is implicated in the renewal and maintenance of ES cells, and has the potential to induce iPS cells, although weaker than KLF4. In this study, we found that inducible deletion of KLF5, specifically in Lgr5+ intestinal epithelial stem cells, suppressed the proliferation and nuclear localization of β-catenin, and generated some apoptotic cells in the intestinal crypts of mice. Furthermore, we demonstrated that inducible deletion of KLF5 in all intestinal epithelia caused mislocalization of Paneth cells, which constitute the stem cell niche. These data indicate that KLF5, rather than KLF4, is required for the maintenance and differentiation of Lgr5+ intestinal stem cells. Moreover, we detected frequent genome amplification at the KLF5 locus in human colorectal cancers (CRCs), and enhanced expression of KLF5 in CRC samples. In mice, Lgr5+ stem cell-specific induction of an active β-catenin mutant generated severe lethal adenomas and carcinomas. By contrast, when the induction of active β-catenin was performed simultaneously with deletion of KLF5 in stem cells, oncogenesis was almost completely suppressed. The simultaneous deletion of KLF5 under the induction of the active mutant of β-catenin in the stem cells suppressed the transcription of HDAC1and Sphk1, which promotes CRCs, and upregulated the transcription of Aim2 and Foxo3, tumor suppressors in CRCs, in both the FACS sorted stem cells and the transit amplifying cells. These results indicate that oncogenesis of intestinal tumors induced by Wnt/β-catenin signal activation (92-97% in CRCs) in stem cells requires KLF5, as in the case of Myc, and that KLF5 is also an essential controlling factor for homeostatic turnover and maintenance, niche formation, and differentiation of the intestinal epithelial stem cells. These suggest that KLF5 is a promising target oncogene for CRC therapy directed at colon cancer stem cells. Citation Format: Takeo Nakaya, Masahiko Kuroda, Ryozo Nagai. KLF5 is essential for oncogenesis of intestinal tumors and control of intestinal stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2293. doi:10.1158/1538-7445.AM2013-2293