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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(Min)), or by Apc(1322T) encoding a partially-func...

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Autores principales: Mieszczanek, Juliusz, van Tienen, Laurens M., Ibrahim, Ashraf E. K., Winton, Douglas J., Bienz, Mariann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374407/
https://www.ncbi.nlm.nih.gov/pubmed/30760710
http://dx.doi.org/10.1038/s41467-018-08164-z
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author Mieszczanek, Juliusz
van Tienen, Laurens M.
Ibrahim, Ashraf E. K.
Winton, Douglas J.
Bienz, Mariann
author_facet Mieszczanek, Juliusz
van Tienen, Laurens M.
Ibrahim, Ashraf E. K.
Winton, Douglas J.
Bienz, Mariann
author_sort Mieszczanek, Juliusz
collection PubMed
description 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(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 β-catenin to the cell surface, but this undesirable effect is not seen in Apc(1322T) 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.
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spelling pubmed-63744072019-02-15 Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models Mieszczanek, Juliusz van Tienen, Laurens M. Ibrahim, Ashraf E. K. Winton, Douglas J. Bienz, Mariann Nat Commun Article 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(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 β-catenin to the cell surface, but this undesirable effect is not seen in Apc(1322T) 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. Nature Publishing Group UK 2019-02-13 /pmc/articles/PMC6374407/ /pubmed/30760710 http://dx.doi.org/10.1038/s41467-018-08164-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mieszczanek, Juliusz
van Tienen, Laurens M.
Ibrahim, Ashraf E. K.
Winton, Douglas J.
Bienz, Mariann
Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
title Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
title_full Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
title_fullStr Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
title_full_unstemmed Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
title_short Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
title_sort bcl9 and pygo synergise downstream of apc to effect intestinal neoplasia in fap mouse models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374407/
https://www.ncbi.nlm.nih.gov/pubmed/30760710
http://dx.doi.org/10.1038/s41467-018-08164-z
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