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A protein interaction between beta-catenin and Dnmt1 regulates Wnt Signaling and DNA methylation in colorectal cancer cells

A protein interaction between beta-catenin and Dnmt1 regulates Wnt Signaling and DNA methylation in colorectal cancer cells
A protein interaction between beta-catenin and Dnmt1 regulates Wnt Signaling and DNA methylation in colorectal cancer cells
Aberrant activation of the Wnt signaling pathway is an important step in the initiation and progression of tumor development in diverse cancers. The central effector of canonical Wnt signaling, beta-catenin (CTNNB1), is a multifunctional protein, and has been extensively studied with respect to its roles in cell-cell adhesion and in regulation of Wnt-driven transcription. Here, a novel mass spectrometry-based proteomics technique in colorectal cancer cells expressing stabilized beta-catenin, was used to identify a protein-protein interaction between beta-catenin and DNA methyltransferase I (Dnmt1) protein, the primary regulator of DNA methylation patterns in mammalian cells. Dnmt1 and beta-catenin strongly co- localized in the nuclei of colorectal cancer cells, and the interaction is mediated by the central domain of the Dnmt1 protein. Dnmt1 protein abundance is dependent upon the levels of beta-catenin, and is increased in cells expressing stabilized mutant beta-catenin. Conversely, the Dnmt1 regulates the levels of nuclear beta-catenin and beta-catenin/TCF driven transcription. In addition, lysine-specific demethylase 1 (LSD1/KDM1A), a regulator of DNMT1 stability, was identified as a component of the Dnmt1/beta-catenin protein complex and perturbation of the Dnmt1/beta-catenin interaction altered DNA methylation. In summary, a functional protein-protein interaction was identified between two critically important oncoproteins, in turn revealing a link between Wnt signaling and downstream nuclear functions mediated by Dnmt1. Implications: Two critical oncoproteins, Dnmt1 and beta-catenin mutually regulate one another's levels and activities in colorectal cancer cells.
1541-7786
Song, Jing
c3f6ccf2-4c63-487c-9c39-e25382b9ee91
Du, Zhanwen
78a06095-e02b-4461-aca6-562ddd99bf84
Ravasz, Mate
c51d3e2c-93f9-4e07-a3ed-e489ffa102bf
Dong, Bohan
95525b85-cd60-4798-99f0-c9039e231d59
Wang, Zhenghe
9142416c-1981-4fa6-9fd7-e0a61a81fc33
Ewing, Rob M
022c5b04-da20-4e55-8088-44d0dc9935ae
Song, Jing
c3f6ccf2-4c63-487c-9c39-e25382b9ee91
Du, Zhanwen
78a06095-e02b-4461-aca6-562ddd99bf84
Ravasz, Mate
c51d3e2c-93f9-4e07-a3ed-e489ffa102bf
Dong, Bohan
95525b85-cd60-4798-99f0-c9039e231d59
Wang, Zhenghe
9142416c-1981-4fa6-9fd7-e0a61a81fc33
Ewing, Rob M
022c5b04-da20-4e55-8088-44d0dc9935ae

Song, Jing, Du, Zhanwen, Ravasz, Mate, Dong, Bohan, Wang, Zhenghe and Ewing, Rob M (2015) A protein interaction between beta-catenin and Dnmt1 regulates Wnt Signaling and DNA methylation in colorectal cancer cells. Molecular Cancer Research. (doi:10.1158/1541-7786.MCR-13-0644). (PMID:25753001)

Record type: Article

Abstract

Aberrant activation of the Wnt signaling pathway is an important step in the initiation and progression of tumor development in diverse cancers. The central effector of canonical Wnt signaling, beta-catenin (CTNNB1), is a multifunctional protein, and has been extensively studied with respect to its roles in cell-cell adhesion and in regulation of Wnt-driven transcription. Here, a novel mass spectrometry-based proteomics technique in colorectal cancer cells expressing stabilized beta-catenin, was used to identify a protein-protein interaction between beta-catenin and DNA methyltransferase I (Dnmt1) protein, the primary regulator of DNA methylation patterns in mammalian cells. Dnmt1 and beta-catenin strongly co- localized in the nuclei of colorectal cancer cells, and the interaction is mediated by the central domain of the Dnmt1 protein. Dnmt1 protein abundance is dependent upon the levels of beta-catenin, and is increased in cells expressing stabilized mutant beta-catenin. Conversely, the Dnmt1 regulates the levels of nuclear beta-catenin and beta-catenin/TCF driven transcription. In addition, lysine-specific demethylase 1 (LSD1/KDM1A), a regulator of DNMT1 stability, was identified as a component of the Dnmt1/beta-catenin protein complex and perturbation of the Dnmt1/beta-catenin interaction altered DNA methylation. In summary, a functional protein-protein interaction was identified between two critically important oncoproteins, in turn revealing a link between Wnt signaling and downstream nuclear functions mediated by Dnmt1. Implications: Two critical oncoproteins, Dnmt1 and beta-catenin mutually regulate one another's levels and activities in colorectal cancer cells.

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Accepted/In Press date: 26 January 2015
Published date: 9 March 2015
Organisations: Molecular and Cellular, Biomedicine

Identifiers

Local EPrints ID: 376398
URI: https://eprints.soton.ac.uk/id/eprint/376398
ISSN: 1541-7786
PURE UUID: f123c589-f4ec-440f-9d70-49d82e222214
ORCID for Rob M Ewing: ORCID iD orcid.org/0000-0001-6510-4001

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Date deposited: 28 Apr 2015 11:00
Last modified: 18 Jul 2019 00:40

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