Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine.
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.
Höglund
Andreas
A
Department of Molecular Biology, Umeå University, Umeå, Sweden.
Nilsson
Lisa M
LM
Forshell
Linus Plym
LP
Maclean
Kirsteen H
KH
Nilsson
Jonas A
JA
D000782:Aneuploidy; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002453:Cell Cycle; D004249:DNA Damage; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D004273:DNA, Neoplasm / Q000187:drug effects; D000077209:Decitabine; D004622:Embryo, Mammalian; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000473:pathology / Q000821:virology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine