Epigenetic reprogramming of cancer cells via targeted DNA methylation
Epigenetic reprogramming of cancer cells via targeted DNA methylation
复制标题
DOI：
10.4161/epi.19507
复制
发表时间：
2012-04-01
期刊：
影响因子：
3.7
通讯作者：
Blancafort, Pilar
中科院分区：
文献类型：
--
作者：
Rivenbark, Ashley G.;Stolzenburg, Sabine;Blancafort, Pilar
治疗癌症等人类疾病的一个障碍是无法选择性且有效地靶向历史上不可成药的靶标，例如转录因子。在这里，我们采用了一种新技术，利用人工转录因子（ATF）来表观遗传地靶向癌细胞中的基因表达。我们发现，通过锌指 ATF 将 DNA 甲基转移酶 3a (DNMT3a) 靶向这些基因的启动子，可以在乳腺癌细胞中实现位点特异性 DNA 甲基化以及对肿瘤抑制因子 Maspin 和癌基因 SOX2 的长期稳定抑制。使用这种方法，我们发现与瞬时敲低相比，Maspin 和 SOX2 下调更为显着，同时还伴随着癌细胞的稳定表型重编程。这些发现表明，与表观遗传编辑域相关的多模块锌指蛋白可以用作新的细胞资源，以选择性和遗传性地改变基因表达模式，从而稳定地重新编程细胞命运。
An obstacle in the treatment of human diseases such as cancer is the inability to selectively and effectively target historically undruggable targets such as transcription factors. Here, we employ a novel technology using artificial transcription factors (ATFs) to epigenetically target gene expression in cancer cells. We show that site-specific DNA methylation and long-term stable repression of the tumor suppressor Maspin and the oncogene SOX2 can be achieved in breast cancer cells via zinc-finger ATFs targeting DNA methyltransferase 3a (DNMT3a) to the promoters of these genes. Using this approach, we show Maspin and SOX2 downregulation is more significant as compared with transient knockdown, which is also accompanied by stable phenotypic reprogramming of the cancer cell. These findings indicate that multimodular Zinc Finger Proteins linked to epigenetic editing domains can be used as novel cell resources to selectively and heritably alter gene expression patterns to stably reprogram cell fate.