Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dysregulation of epithelial-mesenchymal transition and subcellular re-localization of Beta-Catenin
Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dysregulation of epithelial-mesenchymal transition and subcellular re-localization of Beta-Catenin
DNA methyltransferase I plays the central role in maintenance of CpG DNA methylation patterns across the genome and alteration of CpG methylation patterns is a frequent and significant occurrence across many cancers. Cancer cells carrying hypomorphic alleles of Dnmt1 have become important tools for understanding Dnmt1 function and CpG methylation. In this study, we analyse colorectal cancer cells with a homozygous deletion of exons 3 to 5 of Dnmt1, resulting in reduced Dnmt1 activity. Although this cell model has been widely used to study the epigenome, the effects of the Dnmt1 hypomorph on cell signalling pathways and the wider proteome are largely unknown. In this study, we perform the first quantitative proteomic analysis of this important cell model and identify multiple signalling pathways and processes that are significantly dysregulated in the hypomorph cells. In Dnmt1 hypomorph cells, we observed a clear and unexpected signature of increased Epithelial-to-Mesenchymal transition (EMT) markers as well as reduced expression and sub-cellular re-localization of Beta-Catenin. Expression of wild-type Dnmt1 in hypomorph cells or knock-down of wild-type Dnmt1 did not recapitulate or rescue the observed protein profiles in Dnmt1 hypomorph cells suggesting that hypomorphic Dnmt1 causes changes not solely attributable to Dnmt1 protein levels. In summary, we present the first comprehensive proteomic analysis of the widely studied Dnmt1 hypomorph colorectal cancer cells and identify redistribution of Dnmt1 and its interaction partner Beta-Catenin.
DNA methyltransferase, Beta-Catenin, epithelial-mesenchymal transition, proteomics
107-121
Bowler, Emily H.
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Smith-Vidal, Alex
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Lester, Alex
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Bell, Joseph
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Wang, Zhenghe
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Bell, Christopher
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Wang, Yihua
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Divecha, Nullin
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Skipp, Paul
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Ewing, Rob M.
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27 August 2019
Bowler, Emily H.
af2391ca-58c3-4b8b-b31b-2a7751577bd8
Smith-Vidal, Alex
01b7c44e-5128-407a-b7ab-1d2da261e608
Lester, Alex
a9c1a2dd-b5e4-476a-ba30-da378eba4042
Bell, Joseph
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Wang, Zhenghe
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Bell, Christopher
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Wang, Yihua
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Divecha, Nullin
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Skipp, Paul
1ba7dcf6-9fe7-4b5c-a9d0-e32ed7f42aa5
Ewing, Rob M.
022c5b04-da20-4e55-8088-44d0dc9935ae
Bowler, Emily H., Smith-Vidal, Alex, Lester, Alex, Bell, Joseph, Wang, Zhenghe, Bell, Christopher, Wang, Yihua, Divecha, Nullin, Skipp, Paul and Ewing, Rob M.
(2019)
Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dysregulation of epithelial-mesenchymal transition and subcellular re-localization of Beta-Catenin.
Epigenetics, 15 (1-2), .
(doi:10.1080/15592294.2019.1656154).
Abstract
DNA methyltransferase I plays the central role in maintenance of CpG DNA methylation patterns across the genome and alteration of CpG methylation patterns is a frequent and significant occurrence across many cancers. Cancer cells carrying hypomorphic alleles of Dnmt1 have become important tools for understanding Dnmt1 function and CpG methylation. In this study, we analyse colorectal cancer cells with a homozygous deletion of exons 3 to 5 of Dnmt1, resulting in reduced Dnmt1 activity. Although this cell model has been widely used to study the epigenome, the effects of the Dnmt1 hypomorph on cell signalling pathways and the wider proteome are largely unknown. In this study, we perform the first quantitative proteomic analysis of this important cell model and identify multiple signalling pathways and processes that are significantly dysregulated in the hypomorph cells. In Dnmt1 hypomorph cells, we observed a clear and unexpected signature of increased Epithelial-to-Mesenchymal transition (EMT) markers as well as reduced expression and sub-cellular re-localization of Beta-Catenin. Expression of wild-type Dnmt1 in hypomorph cells or knock-down of wild-type Dnmt1 did not recapitulate or rescue the observed protein profiles in Dnmt1 hypomorph cells suggesting that hypomorphic Dnmt1 causes changes not solely attributable to Dnmt1 protein levels. In summary, we present the first comprehensive proteomic analysis of the widely studied Dnmt1 hypomorph colorectal cancer cells and identify redistribution of Dnmt1 and its interaction partner Beta-Catenin.
Text
Dnmt1-hypomorph-Bowler-version-for-pure
- Accepted Manuscript
More information
Accepted/In Press date: 8 August 2019
e-pub ahead of print date: 26 August 2019
Published date: 27 August 2019
Keywords:
DNA methyltransferase, Beta-Catenin, epithelial-mesenchymal transition, proteomics
Identifiers
Local EPrints ID: 433981
URI: http://eprints.soton.ac.uk/id/eprint/433981
ISSN: 1559-2294
PURE UUID: 4adb82df-22ee-4e85-a8b3-b4c9498e4970
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Date deposited: 09 Sep 2019 16:30
Last modified: 06 Jun 2024 04:14
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Contributors
Author:
Emily H. Bowler
Author:
Alex Smith-Vidal
Author:
Joseph Bell
Author:
Zhenghe Wang
Author:
Christopher Bell
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