Submitted October 17, 2008
Accepted January 24, 2009
Myc sensitizes p53 deficient cancer cells to the DNA damaging effects of the DNA methyltransferase inhibitor Decitabine
Andreas Hoglund, Lisa M. Nilsson, Linus Plym Forshell, Kirsteen H. Maclean, and Jonas A. Nilsson*
Department of Molecular Biology, Umea University, Umea, Sweden
* Corresponding author; email: jonas.nilsson{at}molbiol.umu.se.
Decitabine (also referred to as Dacogen or 5-aza-2'-deoxycytidine) is a drug that has recently been FDA-approved for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL) we discovered that Decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53-/- mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by Decitabine via activation of Chk1. This triggers aneuploidy and cell death which correlates with, but can occur in the absence of, EBV reactivation, caspase activation and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that Decitabine constitutes a potential new drug against lymphoma which would selectively sensitize tumor cells but spare normal tissue.
