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DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis

The ERK signalling pathway regulates key cell fate decisions in the intestinal epithelium and is frequently dysregulated in colorectal cancers (CRCs). Variations in the dynamics of ERK activation can induce different biological outcomes and are regulated by multiple mechanisms, including activation...

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Autores principales: Tögel, Lars, Nightingale, Rebecca, Wu, Rui, Chüeh, Anderly C., Al-Obaidi, Sheren, Luk, Ian, Dávalos-Salas, Mercedes, Chionh, Fiona, Murone, Carmel, Buchanan, Daniel D., Chatterton, Zac, Sieber, Oliver M., Arango, Diego, Tebbutt, Niall C., Williams, David, Dhillon, Amardeep S., Mariadason, John M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788859/
https://www.ncbi.nlm.nih.gov/pubmed/29379130
http://dx.doi.org/10.1038/s41598-018-20176-9
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author Tögel, Lars
Nightingale, Rebecca
Wu, Rui
Chüeh, Anderly C.
Al-Obaidi, Sheren
Luk, Ian
Dávalos-Salas, Mercedes
Chionh, Fiona
Murone, Carmel
Buchanan, Daniel D.
Chatterton, Zac
Sieber, Oliver M.
Arango, Diego
Tebbutt, Niall C.
Williams, David
Dhillon, Amardeep S.
Mariadason, John M.
author_facet Tögel, Lars
Nightingale, Rebecca
Wu, Rui
Chüeh, Anderly C.
Al-Obaidi, Sheren
Luk, Ian
Dávalos-Salas, Mercedes
Chionh, Fiona
Murone, Carmel
Buchanan, Daniel D.
Chatterton, Zac
Sieber, Oliver M.
Arango, Diego
Tebbutt, Niall C.
Williams, David
Dhillon, Amardeep S.
Mariadason, John M.
author_sort Tögel, Lars
collection PubMed
description The ERK signalling pathway regulates key cell fate decisions in the intestinal epithelium and is frequently dysregulated in colorectal cancers (CRCs). Variations in the dynamics of ERK activation can induce different biological outcomes and are regulated by multiple mechanisms, including activation of negative feedback loops involving transcriptional induction of dual-specificity phosphatases (DUSPs). We have found that the nuclear ERK-selective phosphatase DUSP5 is downregulated in colorectal tumours and cell lines, as previously observed in gastric and prostate cancer. The DUSP5 promoter is methylated in a subset of CRC cell lines and primary tumours, particularly those with a CpG island methylator phenotype (CIMP). However, this epigenetic change alone could not account for reduced DUSP5 expression in CRC cells. Functionally, DUSP5 depletion failed to alter ERK signalling or proliferation in CRC cell lines, and its transgenic overexpression in the mouse intestine had minimal impact on normal intestinal homeostasis or tumour development. Our results suggest that DUSP5 plays a limited role in regulating ERK signalling associated with the growth of colorectal tumours, but that methylation the DUSP5 gene promoter can serve as an additional means of identifying CIMP-high colorectal cancers.
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spelling pubmed-57888592018-02-08 DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis Tögel, Lars Nightingale, Rebecca Wu, Rui Chüeh, Anderly C. Al-Obaidi, Sheren Luk, Ian Dávalos-Salas, Mercedes Chionh, Fiona Murone, Carmel Buchanan, Daniel D. Chatterton, Zac Sieber, Oliver M. Arango, Diego Tebbutt, Niall C. Williams, David Dhillon, Amardeep S. Mariadason, John M. Sci Rep Article The ERK signalling pathway regulates key cell fate decisions in the intestinal epithelium and is frequently dysregulated in colorectal cancers (CRCs). Variations in the dynamics of ERK activation can induce different biological outcomes and are regulated by multiple mechanisms, including activation of negative feedback loops involving transcriptional induction of dual-specificity phosphatases (DUSPs). We have found that the nuclear ERK-selective phosphatase DUSP5 is downregulated in colorectal tumours and cell lines, as previously observed in gastric and prostate cancer. The DUSP5 promoter is methylated in a subset of CRC cell lines and primary tumours, particularly those with a CpG island methylator phenotype (CIMP). However, this epigenetic change alone could not account for reduced DUSP5 expression in CRC cells. Functionally, DUSP5 depletion failed to alter ERK signalling or proliferation in CRC cell lines, and its transgenic overexpression in the mouse intestine had minimal impact on normal intestinal homeostasis or tumour development. Our results suggest that DUSP5 plays a limited role in regulating ERK signalling associated with the growth of colorectal tumours, but that methylation the DUSP5 gene promoter can serve as an additional means of identifying CIMP-high colorectal cancers. Nature Publishing Group UK 2018-01-29 /pmc/articles/PMC5788859/ /pubmed/29379130 http://dx.doi.org/10.1038/s41598-018-20176-9 Text en © The Author(s) 2018 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
Tögel, Lars
Nightingale, Rebecca
Wu, Rui
Chüeh, Anderly C.
Al-Obaidi, Sheren
Luk, Ian
Dávalos-Salas, Mercedes
Chionh, Fiona
Murone, Carmel
Buchanan, Daniel D.
Chatterton, Zac
Sieber, Oliver M.
Arango, Diego
Tebbutt, Niall C.
Williams, David
Dhillon, Amardeep S.
Mariadason, John M.
DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
title DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
title_full DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
title_fullStr DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
title_full_unstemmed DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
title_short DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
title_sort dusp5 is methylated in cimp-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788859/
https://www.ncbi.nlm.nih.gov/pubmed/29379130
http://dx.doi.org/10.1038/s41598-018-20176-9
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