RRC ID 34766
Author Sakamaki A, Katsuragi Y, Otsuka K, Tomita M, Obata M, Iwasaki T, Abe M, Sato T, Ochiai M, Sakuraba Y, Aoyagi Y, Gondo Y, Sakimura K, Nakagama H, Mishima Y, Kominami R.
Title Bcl11b SWI/SNF-complex subunit modulates intestinal adenoma and regeneration after γ-irradiation through Wnt/β-catenin pathway.
Journal Carcinogenesis
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.
Volume 36(6)
Pages 622-31
Published 2015-6-1
DOI 10.1093/carcin/bgv044
PII bgv044
PMID 25827435
MeSH Adenoma / classification Adenoma / genetics Animals Caco-2 Cells Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic / genetics* Chromosomal Proteins, Non-Histone / genetics* Colonic Neoplasms / classification Colonic Neoplasms / genetics* Cyclin D1 / biosynthesis HCT116 Cells HEK293 Cells Humans Intestinal Mucosa / metabolism Intestinal Mucosa / radiation effects Mice Mice, Inbred C57BL Mice, Knockout Polymorphism, Single Nucleotide Proto-Oncogene Proteins c-myc / biosynthesis Receptors, G-Protein-Coupled / biosynthesis Repressor Proteins / biosynthesis Repressor Proteins / genetics* Transcription Factors / genetics* Tumor Suppressor Proteins / biosynthesis Tumor Suppressor Proteins / genetics* Wnt Proteins / metabolism Wnt Signaling Pathway beta Catenin / biosynthesis beta Catenin / genetics beta Catenin / metabolism*
IF 4.603
Times Cited 10
Mice RBRC02228