Brg1 loss attenuates aberrant wnt-signalling and prevents wnt-dependent tumourigenesis in the murine small intestine.
- Author(s)
- Holik, AZ; Young, M; Krzystyniak, J; Williams, GT; Metzger, D; Shorning, BY; Clarke, AR;
- Details
- Publication Year 2014-07,Volume 10,Issue #7,Page e1004453
- Journal Title
- PLoS genetics
- Publication Type
- Journal Article
- 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.
- Publisher
- PubMed
- Research Division(s)
- Stem Cells And Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov.ezp.lib.unimelb.edu.au/pmc/articles/PMC4091792/
- Publisher's Version
- https://doi.org/10.1371/journal.pgen.1004453
- Terms of Use/Rights Notice
- Copyright: © 2014 Holik et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Creation Date: 2014-07-30 02:50:02