Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias, HUCA, Universidad de Oviedo, Oviedo, Spain.
Eur J Cancer. 2012 Sep;48(14):2270-81. doi: 10.1016/j.ejca.2011.12.019. Epub 2012 Jan 13.
Altered promoter DNA methylation, one of the most important molecular alterations in cancer, is proposed to correlate with deregulation of DNA methyltransferases, although the molecular mechanisms implicated are still poorly understood. Here we show that the de novo DNA methyltransferase DNMT3B is frequently repressed in human colorectal cancer cell lines (CCL) and primary tumours by aberrant DNA hypermethylation of its distal promoter. At the epigenome level, DNMT3B promoter hypermethylation was associated with the hypomethylation of gene promoters usually hypermethylated in the healthy colon. Forced DNMT3B overexpression in cancer cells restored the methylation levels of these promoters in the healthy colon. Our results show a new molecular mechanism of aberrant DNMT3B regulation in colon cancer and suggest that its expression is associated with the methylation of constitutively hypermethylated promoters in the healthy colon.
改变的启动子 DNA 甲基化，癌症中最重要的分子改变之一，被认为与 DNA 甲基转移酶的失调相关，尽管涉及的分子机制仍知之甚少。在这里，我们显示在人类结直肠癌细胞系 (CCL) 和原发肿瘤中，从头 DNA 甲基转移酶 DNMT3B 经常通过其远端启动子的异常 DNA 高甲基化而受到抑制。在表观基因组水平上，DNMT3B 启动子高甲基化与健康结肠中通常高甲基化的基因启动子的低甲基化有关。在癌细胞中强制过表达 DNMT3B 可恢复健康结肠中这些启动子的甲基化水平。我们的结果显示了结直肠癌中异常 DNMT3B 调节的新分子机制，并表明其表达与健康结肠中组成性高甲基化启动子的甲基化有关。
