The depletion of DNA methyltransferase-1 and the epigenetic effects of 5-aza-2’deoxycytidine (decitabine) are differentially regulated by cell cycle progression

摘要: 5-Aza-2'-deoxycytidine (decitabine) is a drug targeting the epigenetic abnormalities of tumors. The basis for its limited efficacy in solid tumors unresolved, but may relate to their indolent growth, p53 genotype or both. We report that primary molecular mechanism decitabine-depletion DNA methyltransferase-1 following "suicide" inactivation-is not absolutely associated with cell cycle progression HCT 116 colon cancer cells, genotype. Control experiments affirmed secondary effects decitabine on global and promoter-specific CpG methylation MAGE-A1 mRNA expression were S-phase dependent, as expected. Secondary changes occurred only growing cells ~24-48 h after treatment; these coincided accumulation, an index damage. Conversely, depletion began immediately single exposure 300 nM it progressed completion within ~8 h, even confluent arrested G 1 2/M. Our results suggest repair remodeling activity arrested, be sufficient support action decitabine, while secondary, require through S-phase.