| First Author | Mieszczanek J | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 724 |
| PubMed ID | 30760710 | Mgi Jnum | J:273354 |
| Mgi Id | MGI:6286873 | Doi | 10.1038/s41467-018-08164-z |
| Citation | Mieszczanek J, et al. (2019) Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models. Nat Commun 10(1):724 |
| abstractText | 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. |
