An essential role for DNA methyltransferase 3a in melanoma tumorigenesis
An essential role for DNA methyltransferase 3a in melanoma tumorigenesis
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DOI：
10.1016/j.bbrc.2009.07.093
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发表时间：
2009-09-25
影响因子：
3.1
通讯作者：
Fei, Jian
中科院分区：
文献类型：
--
作者：
Deng, Tao;Kuang, Ying;Fei, Jian
异常DNA甲基化和相关的肿瘤抑制基因沉默在许多类型的癌症中是常见的。在三种协调的DNA甲基转移酶（Din-tits）中，Dnmt 1和Dnmt 3b都被证明对癌细胞存活和肿瘤发生重要。然而，Dnmt 3a与肿瘤发生的关系在很大程度上仍然未知。在这里，我们表明，抑制Dnmt 3a的表达，通过稳定转染的Dnmt 3a-RNA干扰（RNAi）构建体显着抑制小鼠黑色素瘤模型中的黑色素瘤生长和转移。微阵列分析显示，对肿瘤免疫反应至关重要的基因与黑色素瘤生长的抑制有关。I类和II类MHC基因簇、II类反式激活因子（Ciita）以及5种趋化因子（Cxcl 9、Cxcl 16、Ccl 12、Ccl 4和Ccl 2）的子集的表达上调。此外，我们确定Ciita的启动子IV在Dnmt 3a耗尽的肿瘤中显著去甲基化。此外，几个已知的肿瘤相关基因，这是关键的发育过程和细胞周期，被证实是失调，包括TgfB 1，Socs 1，Socs 2，E2 F6，Cene 1和Cyr 61。本报告中呈现的结果强烈表明，Dnmt 3a在黑色素瘤肿瘤发生中起着所有重要作用，并且潜在机制包括肿瘤免疫应答的调节以及其他过程。(C)2009 Elsevier Inc. All rights reserved.
Abnormal DNA methylation and associated silencing Of tumor suppressor genes are common to many types of cancers. Among the three coordinate DNA methyltransferases (Din-tits), Dnmt1 and Dnmt3b were both shown to be important for cancer cell survival and tumorigenesis. However, the relationship between Dnmt3a and tumorigenesis is still largely Unknown. Here, we show that inhibition of Dnmt3a expression, by stable transfection of a Dnmt3a-RNA interference (RNAi) construct dramatically inhibited melanoma growth and metastasis in mouse melanoma models. Microarray analysis revealed that genes critical for the tumor immune response, were implicated in the inhibition of melanoma growth. Expression of a cluster of class I and class II MHC genes, class II transactivator (Ciita), as well as a subset of 5 chemokines (Cxcl9, Cxcl16, Ccl12, Ccl4, and Ccl2) were up-regulated. Furthermore, we determined that the promoter IV of Ciita was significantly demethylated in Dnmt3a-depleted tumors. In addition, several known tumor-related genes, which are critical for developmental processes and cell cycle, were confirmed to be misregulated, including TgfB1, Socs1, Socs2, E2F6, Cene1, and Cyr61. The results presented in this report strongly suggest that Dnmt3a plays all essential role in melanoma tumorigenesis, and that the Underlying mechanisms include the modulation of the tumor immune response, as well as Other processes. (C) 2009 Elsevier Inc. All rights reserved.