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Brg1 loss attenuates aberrant Wnt-signalling and prevents Wnt-dependent tumourigenesis in the murine small intestine

Holik, Aliaksei Z., Young, Madeleine, Krzystyniak, Joanna, Williams, Geraint Trefor, Metzger, Daniel, Shorning, Boris and Clarke, Alan Richard 2014. Brg1 loss attenuates aberrant Wnt-signalling and prevents Wnt-dependent tumourigenesis in the murine small intestine. PLoS Genetics 10 (7) , e1004453. 10.1371/journal.pgen.1004453

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QR Microbiology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Public Library of Science
ISSN: 1553-7404
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 9 January 2014
Last Modified: 19 Feb 2019 16:42
URI: http://orca.cf.ac.uk/id/eprint/64495

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