The depletion of DNA methyltransferase-1 and the epigenetic effects of 5-aza-2′deoxycytidine (decitabine) are differentially regulated by cell cycle progression
The depletion of DNA methyltransferase-1 and the epigenetic effects of 5-aza-2′deoxycytidine (decitabine) are differentially regulated by cell cycle progression
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DOI：
10.4161/epi.6.8.16064
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发表时间：
2011-08-01
期刊：
影响因子：
3.7
通讯作者：
Fitzpatrick, F. A.
中科院分区：
文献类型：
--
作者：
Al-Salihi, Mazin;Yu, Margaret;Fitzpatrick, F. A.
5-氮杂-2 '-脱氧胞苷（地西他滨）是一种靶向肿瘤表观遗传异常的药物。其在实体瘤中的有限疗效的基础尚未解决，但可能与其惰性生长，其p53基因型或两者有关。我们报告的主要分子机制，地西他滨的DNA甲基转移酶-1耗尽后，其“自杀”失活，是不是绝对与HCT 116结肠癌细胞的细胞周期进展，但与他们的p53基因型。对照实验证实，地西他滨对整体和启动子特异性CpG甲基化和MAGE-A1 mRNA表达的次级分子效应是S期依赖性的，正如预期的那样。CpG甲基化的继发性变化仅发生在生长中的细胞中，类似于地西他滨处理后24-48小时;这些表观遗传变化与p53积累一致，这是DNA损伤的指标。相反，在单次暴露于300 nM地西他滨后，DNA甲基转移酶-1的初级消耗立即开始，并且在类似于8小时内进展至完成，即使在G（1）和G（2）/M中停滞的融合细胞中也是如此。我们的研究结果表明，DNA修复和重塑活动逮捕，融合细胞可能足以支持地西他滨的主要分子作用，而其次要的，表观遗传效应需要通过S期的细胞周期进展。
5-Aza-2'-deoxycytidine (decitabine) is a drug targeting the epigenetic abnormalities of tumors. The basis for its limited efficacy in solid tumors is unresolved, but may relate to their indolent growth, their p53 genotype or both. We report that the primary molecular mechanism of decitabine-depletion of DNA methyltransferase-1 following its "suicide" inactivation-is not absolutely associated with cell cycle progression in HCT 116 colon cancer cells, but is associated with their p53 genotype. Control experiments affirmed that the secondary molecular effects of decitabine on global and promoter-specific CpG methylation and MAGE-A1 mRNA expression were S-phase dependent, as expected. Secondary changes in CpG methylation occurred only in growing cells similar to 24-48 h after decitabine treatment; these epigenetic changes coincided with p53 accumulation, an index of DNA damage. Conversely, primary depletion of DNA methyltransferase-1 began immediately after a single exposure to 300 nM decitabine and it progressed to completion within similar to 8 h, even in confluent cells arrested in G(1) and G(2)/M. Our results suggest that DNA repair and remodeling activity in arrested, confluent cells may be sufficient to support the primary molecular action of decitabine, while its secondary, epigenetic effects require cell cycle progression through S-phase.