Brg1 Loss Attenuates Aberrant Wnt-Signalling and Prevents Wnt-Dependent Tumourigenesis in the Murine Small Intestine
AuthorHolik, AZ; Young, M; Krzystyniak, J; Williams, GT; Metzger, D; Shorning, BY; Clarke, AR
Source TitlePLoS Genetics
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sHOLIK, ALIAKSEI
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsHolik, A. Z., Young, M., Krzystyniak, J., Williams, G. T., Metzger, D., Shorning, B. Y. & Clarke, A. R. (2014). Brg1 Loss Attenuates Aberrant Wnt-Signalling and Prevents Wnt-Dependent Tumourigenesis in the Murine Small Intestine. PLOS GENETICS, 10 (7), https://doi.org/10.1371/journal.pgen.1004453.
Access StatusOpen Access
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.
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