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PMID:19179467

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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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MYC

involved_in

GO:0071466: cellular response to xenobiotic stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(CHEBI:50131)

Seeded From UniProt

complete

MOUSE:MYC

involved_in

GO:0071466: cellular response to xenobiotic stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(CHEBI:50131)

Seeded From UniProt

complete

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


See also

References

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