PMID:19179467

Citation	Höglund, A, Nilsson, LM, Forshell, LP, Maclean, KH and Nilsson, JA (2009) Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine. Blood 113:4281-8
Abstract	Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) 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 that correlates with, but can occur in the absence of, Epstein-Barr virus (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 that would selectively sensitize tumor cells but spare normal tissue.
Links	PubMed Online version:10.1182/blood-2008-10-183475
Keywords	Aneuploidy; Animals; Antimetabolites, Antineoplastic/pharmacology; Apoptosis/drug effects; Azacitidine/analogs & derivatives; Azacitidine/pharmacology; Blotting, Western; Burkitt Lymphoma/metabolism; Burkitt Lymphoma/pathology; Burkitt Lymphoma/virology; Cell Cycle; DNA Damage; DNA Methylation; DNA Modification Methylases/antagonists & inhibitors; DNA, Neoplasm/drug effects; Embryo, Mammalian; Epstein-Barr Virus Infections/genetics; Epstein-Barr Virus Infections/pathology; Epstein-Barr Virus Infections/virology; Fibroblasts/cytology; Fibroblasts/metabolism; Herpesvirus 4, Human/isolation & purification; Humans; Kidney/cytology; Kidney/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation/genetics; Proto-Oncogene Proteins c-myc/physiology; Tumor Suppressor Protein p53/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MYC	involved_in	GO:2001022: positive regulation of response to DNA damage stimulus	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MYC	involved_in	GO:0043280: positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MYC	involved_in	GO:0035690: cellular response to drug	ECO:0000314: direct assay evidence used in manual assertion		P	has_input:(CHEBI:50131)	Seeded From UniProt	complete
HUMAN:MYC	involved_in	GO:0010332: response to gamma radiation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:MYC	involved_in	GO:0035690: cellular response to drug	ECO:0000314: direct assay evidence used in manual assertion		P	has_input:(CHEBI:50131)	Seeded From UniProt	complete

References

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