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Cell Rep. 2014 Dec 11;9(5):1827-1840. doi: 10.1016/j.celrep.2014.10.063. Epub 2014 Nov 26.

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

Author information

1
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: charles-brenner@uiowa.edu.

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.

PMID:
25466250
PMCID:
PMC4268240
DOI:
10.1016/j.celrep.2014.10.063
[Indexed for MEDLINE]
Free PMC Article

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