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

Author

Listed:
  • Juliusz Mieszczanek

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Laurens M. Tienen

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Ashraf E. K. Ibrahim

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Douglas J. Winton

    (University of Cambridge, Li Ka Shing Centre,)

  • Mariann Bienz

    (Cambridge Biomedical Campus, Francis Crick Avenue)

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.

Suggested Citation

  • Juliusz Mieszczanek & Laurens M. Tienen & Ashraf E. K. Ibrahim & Douglas J. Winton & Mariann Bienz, 2019. "Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08164-z
    DOI: 10.1038/s41467-018-08164-z
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    Cited by:

    1. Hongyang Wang & Mariann Bienz & Xiao-Xue Yan & Wenqing Xu, 2023. "Structural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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