title: Bcl11b SWI/SNF-complex subunit modulates intestinal adenoma and regeneration after γ-irradiation through Wnt/β-catenin pathway.
abstract: SWI/SNF chromatin remodeling complexes constitute a highly related family of multi-subunit complexes to modulate transcription, and SWI/SNF subunit genes are collectively mutated in 20% of all human cancers. Bcl11b is a SWI/SNF subunit and acts as a haploinsufficient tumor suppressor in leukemia/lymphomas. Here, we show expression of Bcl11b in intestinal crypt cells and promotion of intestinal tumorigenesis by Bcl11b attenuation in Apc (min/+) mice. Of importance, mutations or allelic loss of BCL11B was detected in one-third of human colon cancers. We also show that attenuated Bcl11b activity in the crypt base columnar (CBC) cells expressing the Lgr5 stem cell marker enhanced regeneration of intestinal epithelial cells after the radiation-induced injury. Interestingly, BCL11B introduction in human cell lines downregulated transcription of β-catenin target genes, whereas Bcl11b attenuation in Lgr5(+) CBCs increased expression of β-catenin targets including c-Myc and cyclin D1. Together, our results argue that Bcl11b impairment promotes tumor development in mouse and human intestine at least in part through deregulation of β-catenin pathway.
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sakamaki
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsuragi
authors.affiliation: Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Otsuka
authors.affiliation: Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tomita
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Obata
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and.
authors.forename: Masako
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakuraba
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Aoyagi
authors.affiliation: RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan ymishima@med.niigata-u.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae-shi, Tokyo, 201-8511, Japan, Brain Research Institute, Niigata University, Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan, Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kominami
mesh_terms: D000236:Adenoma / Q000145:classification / Q000235:genetics; D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D003110:Colonic Neoplasms / Q000145:classification / Q000235:genetics*; D019938:Cyclin D1 / Q000096:biosynthesis; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C479740:BCL11B protein, human; D002868:Chromosomal Proteins, Non-Histone; C116884:LGR5 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1