Mitochondrial regulation of cancer associated nuclear DNA methylation.
Mitochondrial regulation of cancer associated nuclear DNA methylation.
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DOI：
10.1016/j.bbrc.2007.10.047
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发表时间：
2007-12
影响因子：
3.1
通讯作者：
Cheng-hui Xie;A. Naito;T. Mizumachi;T. Evans;M. Douglas;C. Cooney;C. Fan;M. Higuchi
中科院分区：
文献类型：
--
作者：
Cheng-hui Xie;A. Naito;T. Mizumachi;T. Evans;M. Douglas;C. Cooney;C. Fan;M. Higuchi
癌症的发生和发展与特定基因的甲基化依赖性沉默有关，但其机制及其调控尚未确定。我们先前证明线粒体DNA含量的减少诱导癌症进展。我们发现线粒体DNA缺陷型LNρ0-8激活了细胞核DNA启动子的超甲基化，包括内皮素B受体、O 6-甲基鸟嘌呤-DNA甲基转移酶和E-钙粘蛋白的启动子CpG岛。这些是未甲基化的，相应的基因产物在含有线粒体DNA的亲本LNCaP中表达。线粒体DNA的缺乏诱导DNA甲基转移酶1的表达，这是负责观察到的甲基化模式。抑制DNA甲基转移酶可消除LNρ0-8中的超甲基化和表达的基因产物。这些研究表明，线粒体DNA的丢失或减少导致DNA甲基转移酶1的诱导，内皮素B受体、O 6-甲基鸟嘌呤-DNA甲基转移酶和E-钙粘蛋白的启动子的高甲基化，以及相应基因产物的减少。
The onset and progression of cancer is associated with the methylation-dependent silencing of specific genes, however, the mechanism and its regulation have not been established. We previously demonstrated that reduction of mitochondrial DNA content induces cancer progression. Here we found that mitochondrial DNA-deficient LNρ0-8 activates the hypermethylation of the nuclear DNA promoters including the promoter CpG islands of the endothelin B receptor, O6-methylguanine-DNA methyltransferase, and E-cadherin. These are unmethylated and the corresponding gene products are expressed in the parental LNCaP containing mitochondrial DNA. The absence of mitochondrial DNA induced DNA methyltransferase 1 expression which was responsible for the methylation patterns observed. Inhibition of DNA methyltransferase eliminated hypermethylation and expressed gene products in LNρ0-8. These studies demonstrate loss or reduction of mitochondrial DNA resulted in the induction of DNA methyltransferase 1, hypermethylation of the promoters of endothelin B receptor, O6-methylguanine-DNA methyltransferase, and E-cadherin, and reduction of the corresponding gene products.