Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation.
Cell Rep
; 9(5): 1827-1840, 2014 Dec 11.
Article
in En
| MEDLINE
| ID: mdl-25466250
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Transformation, Neoplastic
/
Proto-Oncogene Proteins
/
Ras Proteins
/
DNA Methylation
/
DNA-Binding Proteins
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Rep
Year:
2014
Document type:
Article