title: KLF5 regulates the integrity and oncogenicity of intestinal stem cells.
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.
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, 
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakaya
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Masami
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands rnagai@jichi.ac.jp kuroda@tokyo-med.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the Netherlands rnagai@jichi.ac.jp kuroda@tokyo-med.ac.jp.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C492214:KLF5 protein, human; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors