KLF5 regulates the integrity and oncogenicity of intestinal stem cells

Takeo Nakaya, Seishi Ogawa, Ichiro Manabe, Masami Tanaka, Masashi Sanada, Toshiro Sato, Makoto M. Taketo, Kazuki Nakao, Hans Clevers, Masashi Fukayama, Masahiko Kuroda, Ryozo Nagai

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5+ 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 to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5+ stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of β-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of β-catenin in Lgr5+ stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/β-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.

Original languageEnglish
Pages (from-to)2882-2891
Number of pages10
JournalCancer Research
Volume74
Issue number10
DOIs
Publication statusPublished - 2014 May 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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