Cargando…
Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression
Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcrip...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613692/ https://www.ncbi.nlm.nih.gov/pubmed/35606410 http://dx.doi.org/10.1038/s41418-022-01016-w |
_version_ | 1784820031330189312 |
---|---|
author | Luk, Ian Y. Jenkins, Laura J. Schoffer, Kael L. Ng, Irvin Tse, Janson W. T. Mouradov, Dmitri Kaczmarczyk, Stanislaw Nightingale, Rebecca Burrows, Allan D. Anderson, Robin L. Arango, Diego Dopeso, Higinio Croft, Larry Richardson, Mark F. Sieber, Oliver M. Liao, Yang Mooi, Jennifer K. Vukelic, Natalia Reehorst, Camilla M. Afshar-Sterle, Shoukat Whitehall, Vicki L. J. Fennell, Lochlan Abud, Helen E. Tebbutt, Niall C. Phillips, Wayne A. Williams, David S. Shi, Wei Mielke, Lisa A. Ernst, Matthias Dhillon, Amardeep S. Clemons, Nicholas J. Mariadason, John M. |
author_facet | Luk, Ian Y. Jenkins, Laura J. Schoffer, Kael L. Ng, Irvin Tse, Janson W. T. Mouradov, Dmitri Kaczmarczyk, Stanislaw Nightingale, Rebecca Burrows, Allan D. Anderson, Robin L. Arango, Diego Dopeso, Higinio Croft, Larry Richardson, Mark F. Sieber, Oliver M. Liao, Yang Mooi, Jennifer K. Vukelic, Natalia Reehorst, Camilla M. Afshar-Sterle, Shoukat Whitehall, Vicki L. J. Fennell, Lochlan Abud, Helen E. Tebbutt, Niall C. Phillips, Wayne A. Williams, David S. Shi, Wei Mielke, Lisa A. Ernst, Matthias Dhillon, Amardeep S. Clemons, Nicholas J. Mariadason, John M. |
author_sort | Luk, Ian Y. |
collection | PubMed |
description | Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcription factors, EHF and CDX1, as a mechanism driving differentiation loss in CRCs. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induced extensive chromatin remodelling, transcriptional re-programming, and differentiation along the enterocytic lineage, leading to reduced growth and metastasis. Strikingly, EHF and CDX1 were also able to reprogramme non-colonic epithelial cells to express colonic differentiation markers. By contrast, inactivation of EHF and CDX1 in well-differentiated CRC cells triggered tumour de-differentiation. Mechanistically, we demonstrate that EHF physically interacts with CDX1 via its PNT domain, and that these transcription factors co-operatively drive transcription of the colonic differentiation marker, VIL1. Compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupted normal colonic differentiation and significantly enhanced colorectal tumour progression. These findings thus reveal a novel mechanism driving epithelial de-differentiation and tumour progression in CRC. |
format | Online Article Text |
id | pubmed-9613692 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96136922022-10-29 Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression Luk, Ian Y. Jenkins, Laura J. Schoffer, Kael L. Ng, Irvin Tse, Janson W. T. Mouradov, Dmitri Kaczmarczyk, Stanislaw Nightingale, Rebecca Burrows, Allan D. Anderson, Robin L. Arango, Diego Dopeso, Higinio Croft, Larry Richardson, Mark F. Sieber, Oliver M. Liao, Yang Mooi, Jennifer K. Vukelic, Natalia Reehorst, Camilla M. Afshar-Sterle, Shoukat Whitehall, Vicki L. J. Fennell, Lochlan Abud, Helen E. Tebbutt, Niall C. Phillips, Wayne A. Williams, David S. Shi, Wei Mielke, Lisa A. Ernst, Matthias Dhillon, Amardeep S. Clemons, Nicholas J. Mariadason, John M. Cell Death Differ Article Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcription factors, EHF and CDX1, as a mechanism driving differentiation loss in CRCs. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induced extensive chromatin remodelling, transcriptional re-programming, and differentiation along the enterocytic lineage, leading to reduced growth and metastasis. Strikingly, EHF and CDX1 were also able to reprogramme non-colonic epithelial cells to express colonic differentiation markers. By contrast, inactivation of EHF and CDX1 in well-differentiated CRC cells triggered tumour de-differentiation. Mechanistically, we demonstrate that EHF physically interacts with CDX1 via its PNT domain, and that these transcription factors co-operatively drive transcription of the colonic differentiation marker, VIL1. Compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupted normal colonic differentiation and significantly enhanced colorectal tumour progression. These findings thus reveal a novel mechanism driving epithelial de-differentiation and tumour progression in CRC. Nature Publishing Group UK 2022-05-23 2022-11 /pmc/articles/PMC9613692/ /pubmed/35606410 http://dx.doi.org/10.1038/s41418-022-01016-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Luk, Ian Y. Jenkins, Laura J. Schoffer, Kael L. Ng, Irvin Tse, Janson W. T. Mouradov, Dmitri Kaczmarczyk, Stanislaw Nightingale, Rebecca Burrows, Allan D. Anderson, Robin L. Arango, Diego Dopeso, Higinio Croft, Larry Richardson, Mark F. Sieber, Oliver M. Liao, Yang Mooi, Jennifer K. Vukelic, Natalia Reehorst, Camilla M. Afshar-Sterle, Shoukat Whitehall, Vicki L. J. Fennell, Lochlan Abud, Helen E. Tebbutt, Niall C. Phillips, Wayne A. Williams, David S. Shi, Wei Mielke, Lisa A. Ernst, Matthias Dhillon, Amardeep S. Clemons, Nicholas J. Mariadason, John M. Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression |
title | Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression |
title_full | Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression |
title_fullStr | Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression |
title_full_unstemmed | Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression |
title_short | Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression |
title_sort | epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the ehf and cdx1 transcription factors drives colorectal cancer progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613692/ https://www.ncbi.nlm.nih.gov/pubmed/35606410 http://dx.doi.org/10.1038/s41418-022-01016-w |
work_keys_str_mv | AT lukiany epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT jenkinslauraj epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT schofferkaell epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT ngirvin epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT tsejansonwt epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT mouradovdmitri epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT kaczmarczykstanislaw epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT nightingalerebecca epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT burrowsalland epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT andersonrobinl epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT arangodiego epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT dopesohiginio epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT croftlarry epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT richardsonmarkf epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT sieberoliverm epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT liaoyang epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT mooijenniferk epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT vukelicnatalia epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT reehorstcamillam epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT afsharsterleshoukat epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT whitehallvickilj epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT fennelllochlan epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT abudhelene epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT tebbuttniallc epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT phillipswaynea epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT williamsdavids epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT shiwei epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT mielkelisaa epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT ernstmatthias epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT dhillonamardeeps epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT clemonsnicholasj epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression AT mariadasonjohnm epithelialdedifferentiationtriggeredbycoordinateepigeneticinactivationoftheehfandcdx1transcriptionfactorsdrivescolorectalcancerprogression |