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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • DNA Methylation*
  • DNA-Binding Proteins / physiology*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genomic Imprinting
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mixed Function Oxygenases
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins / physiology*

Substances

  • DNA-Binding Proteins
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Mixed Function Oxygenases
  • TET1 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins