title: Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation.
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.
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Bo-Kuan
authors.initials: BK
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: charles-brenner@uiowa.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Brenner
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D006899:Mixed Function Oxygenases; D041681:NIH 3T3 Cells; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins