Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation.
نویسندگان
چکیده
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.
منابع مشابه
Intrinsic and extrinsic regulation of DNA methylation during malignant transformation
ii ACKNOWLEDGMENTS First, I would like to thank my mentor, Dr. Charles Brenner. He provided me a great opportunity to get excellent training in his lab with ample freedom and full support. He introduced me to the interesting DNA methylation field, which I plan to keep focusing on in the future. Finally, I would like to thank my family for their patience and encouragement. I appreciate everythin...
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عنوان ژورنال:
- Cell reports
دوره 9 5 شماره
صفحات -
تاریخ انتشار 2014