title: Brg1 loss attenuates aberrant wnt-signalling and prevents wnt-dependent tumourigenesis in the murine small intestine.
abstract: Tumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this interdependency in an in vivo setting and assess the viability of Brg1 as a potential therapeutic target. Using a range of transgenic approaches, we deleted Brg1 in the context of Wnt-activated murine small intestinal epithelium. Pan-epithelial loss of Brg1 using VillinCreERT2 and AhCreERT transgenes attenuated expression of Wnt target genes, including a subset of stem cell-specific genes and suppressed Wnt-driven tumourigenesis improving animal survival. A similar increase in survival was observed when Wnt activation and Brg1 loss were restricted to the Lgr5 expressing intestinal stem cell population. We propose a mechanism whereby Brg1 function is required for aberrant Wnt signalling and ultimately for the maintenance of the tumour initiating cell compartment, such that loss of Brg1 in an Apc-deficient context suppresses adenoma formation. Our results highlight potential therapeutic value of targeting Brg1 and serve as a proof of concept that targeting the cells of origin of cancer may be of therapeutic relevance.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom; Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Aliaksei Z
authors.initials: AZ
authors.lastname: Holik
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Young
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Krzystyniak
authors.affiliation: School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Geraint T
authors.initials: GT
authors.lastname: Williams
authors.affiliation: IGBMC, CNRS UMR7104/INSERM U964/Université de Strasbourg, Illkirch, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Boris Y
authors.initials: BY
authors.lastname: Shorning
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D004265:DNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases