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

ABSTRACT: Bcl9 and Pygo are Wnt enhanceosome components that effect ?-catenin-dependent transcription. Whether they mediate ?-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 ?-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating ?-catenin. Our results demonstrate a key role of the Wnt enhanceosome in ?-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.

SUBMITTER: Mieszczanek J 

PROVIDER: S-EPMC6374407 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature