Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models

Juliusz Mieszczanek, Laurens M. Tienen, Ashraf E. K. Ibrahim, Douglas J. Winton and Mariann Bienz ()
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Juliusz Mieszczanek: Cambridge Biomedical Campus, Francis Crick Avenue
Laurens M. Tienen: Cambridge Biomedical Campus, Francis Crick Avenue
Ashraf E. K. Ibrahim: Cambridge Biomedical Campus, Francis Crick Avenue
Douglas J. Winton: University of Cambridge, Li Ka Shing Centre,
Mariann Bienz: Cambridge Biomedical Campus, Francis Crick Avenue

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Bcl9 and Pygo are Wnt enhanceosome components that effect β-catenin-dependent transcription. Whether they mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (ApcMin), or by Apc1322T encoding a partially-functional Apc truncation commonly found in colorectal carcinomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essentially cures Apc1322T mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in ApcMin mice, apparently via relocating nuclear β-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating β-catenin. Our results demonstrate a key role of the Wnt enhanceosome in β-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.

Date: 2019
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DOI: 10.1038/s41467-018-08164-z

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