Epigenetic control of programmed cell death: inhibition by 5-azacytidine of 1,25-dihydroxyvitamin D3-induced programmed cell death in C6.9 glioma cells
Epigenetic control of programmed cell death: inhibition by 5-azacytidine of 1,25-dihydroxyvitamin D3-induced programmed cell death in C6.9 glioma cells
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DOI：
10.1016/s0047-6374(97)00172-3
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发表时间：
1998-03-16
影响因子：
5.3
通讯作者：
Wion, D
中科院分区：
文献类型：
--
作者：
Canova, C;Chevalier, G;Wion, D
在哺乳动物DNA中，胞嘧啶甲基化特别发生在CpG二核苷酸上。虽然DNA甲基化的全部功能尚未被阐明，但已经确定DNA甲基化是参与基因表达、DNA复制和癌症的重要机制。大鼠胶质瘤C6.9细胞在1,25-二羟基维生素D3 （1,25-D3）治疗后发生程序性细胞死亡（PCD）。因此，这些细胞被用来研究DNA甲基化是否参与PCD的控制。我们发现1,25- d3介导的C6.9细胞PCD被暴露于DNA去甲基化剂5-氮杂胞苷（5-AzaC）和5-氮杂胞苷-2'-脱氧胞苷所抑制。这种效应在去除5-AzaC后的几次细胞分裂中仍然可以检测到，因此，DNA甲基化是PCD的一种表观遗传调控机制。因此，在1,25- d3处理的细胞中检测到的凋亡特征核小体间断裂，在用5-AzaC处理这些细胞后不再观察到。然而，5-AzaC并不能完全抑制C6.9细胞对1,25- d3的反应性，因为c-myc基因的诱导不受影响。这些结果表明，DNA甲基化模式的改变可以通过先前高甲基化基因的表达来抑制1,25- d3介导的PCD，如具有死亡抑制活性的原癌基因、内源性病毒序列，甚至是诱导这些细胞分化状态改变的基因。(C) 1998爱思唯尔科学爱尔兰有限公司
In mammalian DNA cytosine methylation occurs specifically at CpG dinucleotide. Although the full array of function of DNA methylation is yet to be elucidated, it is well established that DNA methylation is an important mechanism involved in gene expression, DNA replication and cancer. Rat glioma C6.9 cells undergo programmed cell death (PCD) after treatment with 1,25-dihydroxyvitamin D3 (1,25-D3). Hence, these cells were used to study whether DNA methylation was involved in the control of PCD. We found that 1,25-D3-mediated PCD of C6.9 cells was suppressed by exposure of the cells to the DNA demethylating agents 5-azacytidine (5-AzaC) and 5-aza-2'-deoxycytidine. This effect remains detectable several cell divisions following removal of 5-AzaC and, therefore, involves DNA methylation as an epigenetic regulatory mechanism of PCD. Accordingly, internucleosomal fragmentation, a feature of apoptosis that is detected in 1,25-D3-treated cells, is no longer observable after treatment of these cells with 5-AzaC. However, 5-AzaC does not totally suppress the responsiveness of C6.9 cells to 1,25-D3 since the induction of the c-myc gene remains unaffected. These results suggest that a change in DNA methylation pattern could suppress 1,25-D3-mediated PCD through the expression of previously hypermethylated genes such as proto-oncogenes with death-repressor activity, endogenous virus sequences or even genes inducing change in the differentiated state of these cells. (C) 1998 Elsevier Science Ireland Ltd.