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

Aliaksei Z Holik,Geraint T Williams,Boris Y Shorning,Daniel Metzger,Madeleine Young,Alan R Clarke,Joanna Krzystyniak,Kent W Hunter

doi:10.1371/journal.pgen.1004453

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.

Highlights

More than 90% of colorectal cancers (CRC) are characterised by aberrant activation of the canonical Wnt/b-catenin pathway, which is proposed to play a major role in the initiation and progression of CRC [1]
Using three different conditional approaches, we find that additional loss of Brg1 from the small intestinal epithelium attenuates the Wnt-dependent phenotype resulting from Apc deletion
Brg1 loss attenuates aberrant Wnt signalling in the murine small intestinal epithelium

Summary

Introduction

More than 90% of colorectal cancers (CRC) are characterised by aberrant activation of the canonical Wnt/b-catenin pathway, which is proposed to play a major role in the initiation and progression of CRC [1]. Despite this clear link between deregulated Wnt signalling and disease, therapies which target the Wnt pathway remain limited [2]. BRG1 has been implicated in a variety of biological processes, in both normal and neoplastic tissues [4,5]. The majority of these studies, both in vitro and in vivo, suggest that BRG1 acts as a tumour suppressor. Studies using Brg knock-out mouse models have shown that heterozygous loss of Brg increases susceptibility to both mammary gland and lung tumourigenesis [10,11]

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