Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-08164-z
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Funding
- Cancer Research UK [C7379/A8709, C7379/A15291, C7379/A24639]
- Medical Research Council [U105192713]
- Clinician Scientist Fellowship from Cancer Research UK
- MRC [MC_U105192713] Funding Source: UKRI
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Bcl9 and Pygo are Wnt enhanceosome components that effect beta-catenin-dependent transcription. Whether they mediate beta-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (Apc(Min)), or by Apc(1322T) 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 Apc(1322T) 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 Apc(Min) mice, apparently via relocating nuclear beta-catenin to the cell surface, but this undesirable effect is not seen in Apc(1322T) mice whose Apc truncation retains partial function in regulating beta-catenin. Our results demonstrate a key role of the Wnt enhanceosome in beta-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.
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