Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18061-6. doi: 10.1073/pnas.1114946108. Epub 2011 Oct 19.
Alterations in DNA methylation have been associated with genome-wide hypomethylation and regional de novo methylation in numerous cancers. De novo methylation is mediated by the de novo methyltransferases Dnmt3a and 3b, but only Dnmt3b has been implicated in promoting cancer by silencing of tumor-suppressor genes. In this study, we have analyzed the role of Dnmt3a in lung cancer by using a conditional mouse tumor model. We show that Dnmt3a deficiency significantly promotes tumor growth and progression but not initiation. Changes in gene expression show that Dnmt3a deficiency affects key steps in cancer progression, such as angiogenesis, cell adhesion, and cell motion, consistent with accelerated and more malignant growth. Our results suggest that Dnmt3a may act like a tumor-suppressor gene in lung tumor progression and may be a critical determinant of lung cancer malignancy.
DNA 甲基化的改变与许多癌症中的全基因组低甲基化和区域新生甲基化有关。新生甲基化是由从头甲基转移酶 Dnmt3a 和 3b 介导的，但只有 Dnmt3b 通过沉默肿瘤抑制基因被牵连促进癌症。在这项研究中，我们通过使用条件性小鼠肿瘤模型分析了 Dnmt3a 在肺癌中的作用。我们表明，Dnmt3a 缺乏显着促进肿瘤生长和进展，但不促进肿瘤起始。基因表达的变化表明，Dnmt3a 缺乏会影响癌症进展的关键步骤，如血管生成、细胞黏附和细胞运动，这与加速和更恶性的生长一致。我们的结果表明，Dnmt3a 可能在肺肿瘤进展中充当肿瘤抑制基因，并且可能是肺癌恶性程度的关键决定因素。
