Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation

Bo-Kuan Wu; Charles Brenner

doi:10.1016/j.celrep.2014.10.063

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Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation

Journal article

Open access

Peer reviewed

Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation

Bo-Kuan Wu and Charles Brenner

Cell reports, Vol.9(5), pp.1827-1840

12/11/2014

DOI: 10.1016/j.celrep.2014.10.063

PMCID: PMC4268240

PMID: 25466250

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https://doi.org/10.1016/j.celrep.2014.10.063View

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Abstract

Hypermethylation-mediated tumor suppressor gene (TSG) silencing is a central epigenetic alteration in RAS-dependent tumorigenesis. Ten-eleven translocation (TET) enzymes can depress DNA methylation by hydroxylation of 5-methylcytosine (5mC) bases to 5-hydroxymethylcytosine (5hmC). Here, we report that suppression of TET1 is required for KRAS-induced DNA hypermethylation and cellular transformation. In distinct nonmalignant cell lines, oncogenic KRAS promotes transformation by inhibiting TET1 expression via the ERK-signaling pathway. This reduces chromatin occupancy of TET1 at TSG promoters, lowers levels of 5hmC, and increases levels of 5mC and 5mC-dependent transcriptional silencing. Restoration of TET1 expression by ERK pathway inhibition or ectopic TET1 reintroduction in KRAS-transformed cells reactivates TSGs and inhibits colony formation. KRAS knockdown increases TET1 expression and diminishes colony-forming ability, whereas KRAS/TET1 double knockdown bypasses the KRAS dependence of KRAS-addicted cancer cells. Thus, suppression of TET1-dependent DNA demethylation is critical for KRAS-mediated transformation.

Gene Expression

Genomic Imprinting

NIH 3T3 Cells

DNA-Binding Proteins - physiology

Proto-Oncogene Proteins p21(ras)

Cell Proliferation

Humans

Gene Expression Regulation, Neoplastic

MAP Kinase Signaling System

Mixed Function Oxygenases

DNA Methylation

Animals

Cell Transformation, Neoplastic - genetics

Proto-Oncogene Proteins - physiology

Mice

ras Proteins - physiology

Details

Title: Subtitle: Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation
Creators: Bo-Kuan Wu - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Charles Brenner - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: charles-brenner@uiowa.edu
Resource Type: Journal article
Publication Details: Cell reports, Vol.9(5), pp.1827-1840
Publisher: United States
DOI: 10.1016/j.celrep.2014.10.063
PMID: 25466250
PMCID: PMC4268240
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: R01 CA075954 / NCI NIH HHS R01CA075954 / NCI NIH HHS
Language: English
Date published: 12/11/2014
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788431002771

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