p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage
p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage
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DOI：
10.1038/sj.onc.1211018
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发表时间：
2008-06-05
期刊：
影响因子：
8
通讯作者：
Gore, S. D.
中科院分区：
文献类型：
--
作者：
Jiemjit, A.;Fandy, T. E.;Gore, S. D.
地西他滨（DAC）和5-阿扎胞苷最近被批准用于治疗骨髓增生异常综合征。DAC和5-阿扎胞苷作为DNA甲基转移酶（DNMT）抑制剂的已知活性之外的药效学作用需要进一步研究。本研究的目的是研究DAC对p21（WAF 1/CIP 1）基因表达的影响。白血病细胞中p21（WAF 1/CIP 1）启动子甲基化分析显示不存在CpG甲基化。然而，DAC以剂量依赖性方式上调p21（WAF 1/CIP 1）表达（艾德（50）= 103.34 nM），并诱导白血病细胞G2/M期细胞周期阻滞。DAC和不同的组蛋白去乙酰化酶抑制剂的顺序应用协同诱导p21（WAF 1/CIP 1）的表达。p21（WAF 1/CIP 1）的上调是PDAC诱导的细胞凋亡（ED 50 = 153 nM）。低剂量DAC以DNMT非依赖性和p53依赖性方式诱导同源HCT 116结肠癌细胞中γ-H2 AX表达（艾德（50）=16.5 nM）和上调p21（WAF 1/CIP 1）。p53反式激活pifithrin-alpha或ATM激酶活性的抑制剂KU-5593或咖啡因废除p21（WAF 1/CIP 1）上调，表明DAC上调p21（WAF 1/CIP 1）是p53和ATM依赖性的白血病细胞。总之，DAC通过DNA损伤/ATM/p53轴以DNMT非依赖性方式上调p21（WAF 1/CIP 1）。
Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21(WAF1/CIP1), a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21(WAF1/CIP1) in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21(WAF1/CIP1) expression in a dose-dependent manner (ED(50) = 103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21(WAF1/CIP1) synergistically. Upregulation of p21(WAF1/CIP1) paralleled DAC-induced apoptosis (ED50 = 153 nM). Low doses of DAC induced gamma-H2AX expression (ED(50) =16.5 nM) and upregulated p21(WAF1/CIP1) in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-alpha or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21(WAF1/CIP1) upregulation, indicating that DAC upregulation of p21(WAF1/CIP1) was p53- and ATM-dependent in leukemia cells. In conclusion, DAC upregulates p21(WAF1/CIP1) in DNMT-independent manner via the DNA damage/ATM/p53 axis.