Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
PLoS One. 2012;7(5):e36125. doi: 10.1371/journal.pone.0036125. Epub 2012 May 1.
Silencing of genes by hypermethylation contributes to cancer progression and has been shown to occur with increased frequency at specific genomic loci. However, the precise mechanisms underlying the establishment and maintenance of aberrant methylation marks are still elusive. The de novo DNA methyltransferase 3B (DNMT3B) has been suggested to play an important role in the generation of cancer-specific methylation patterns. Previous studies have shown that a reduction of DNMT3B protein levels induces antiproliferative effects in cancer cells that were attributed to the demethylation and reactivation of tumor suppressor genes. However, methylation changes have not been analyzed in detail yet. Using RNA interference we reduced DNMT3B protein levels in colon cancer cell lines. Our results confirm that depletion of DNMT3B specifically reduced the proliferation rate of DNMT3B-overexpressing colon cancer cell lines. However, genome-scale DNA methylation profiling failed to reveal methylation changes at putative DNMT3B target genes, even in the complete absence of DNMT3B. These results show that DNMT3B is dispensable for the maintenance of aberrant DNA methylation patterns in human colon cancer cells and they have important implications for the development of targeted DNA methyltransferase inhibitors as epigenetic cancer drugs.
基因的沉默通过 hypermethylation 有助于癌症的发展，并且已经在特定的基因组位置以增加的频率发生。然而，建立和维持异常甲基化标记的确切机制仍然难以捉摸。从头 DNA 甲基转移酶 3B（DNMT3B）已被认为在生成癌症特异性甲基化模式方面发挥重要作用。先前的研究表明，DNMT3B 蛋白水平的降低会在癌细胞中诱导抗增殖作用，这归因于肿瘤抑制基因的去甲基化和重新激活。然而，甲基化变化尚未进行详细分析。使用 RNA 干扰，我们降低了结肠癌细胞系中的 DNMT3B 蛋白水平。我们的结果证实，DNMT3B 的耗竭特异性降低了 DNMT3B 过表达结肠癌细胞系的增殖率。然而，全基因组 DNA 甲基化分析未能揭示假定的 DNMT3B 靶基因的甲基化变化，即使在完全缺乏 DNMT3B 的情况下也是如此。这些结果表明，DNMT3B 在维持人类结肠癌细胞中异常 DNA 甲基化模式方面是可有可无的，并且对开发靶向 DNA 甲基转移酶抑制剂作为表观遗传癌症药物具有重要意义。
