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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Mieszczanek J,van Tienen LM,Ibrahim AEK,Winton DJ,Bienz Mdoi
10.1038/s41467-018-08164-zsubject
Has Abstractpub_date
2019-02-13 00:00:00pages
724issue
1issn
2041-1723pii
10.1038/s41467-018-08164-zjournal_volume
10pub_type
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