KLF5 regulates the integrity and oncogenicity of intestinal stem cells

TY - JOUR

T1 - KLF5 regulates the integrity and oncogenicity of intestinal stem cells

AU - Nakaya, Takeo

AU - Ogawa, Seishi

AU - Manabe, Ichiro

AU - Tanaka, Masami

AU - Sanada, Masashi

AU - Sato, Toshiro

AU - Taketo, Makoto M

AU - Nakao, Kazuki

AU - Clevers, Hans

AU - Fukayama, Masashi

AU - Kuroda, Masahiko

AU - Nagai, Ryozo

N1 - ©2014 American Association for Cancer Research.

PY - 2014/5/15

Y1 - 2014/5/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Transformation, Neoplastic

KW - Colorectal Neoplasms

KW - Humans

KW - Intestine, Small

KW - Kruppel-Like Transcription Factors

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Neoplastic Stem Cells

U2 - 10.1158/0008-5472.CAN-13-2574

DO - 10.1158/0008-5472.CAN-13-2574

M3 - Article

C2 - 24626089

SN - 0008-5472

VL - 74

SP - 2882

EP - 2891

JO - Cancer Research

JF - Cancer Research

IS - 10

ER -