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

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 (Apc), or by Apc 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 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 mice, apparently via relocating nuclear β-catenin to the cell surface, but this undesirable effect is not seen in Apc 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.