Data from <i>ΔDNMT3B</i> Variants Regulate DNA Methylation in a Promoter-Specific Manner

Abstract

<div>Abstract<p>DNA methyltransferase 3B (DNMT3B) is critical in <i>de novo</i> DNA methylation during development and tumorigenesis. We recently reported the identification of a DNMT3B subfamily, ΔDNMT3B, which contains at least seven variants, resulting from alternative pre-mRNA splicing. <i>ΔDNMT3B</i>s are the predominant expression forms of <i>DNMT3B</i> in human lung cancer. A strong correlation was observed between the promoter methylation of <i>RASSF1A</i> gene but not <i>p16</i> gene (both frequently inactivated by promoter methylation in lung cancer) and expression of <i>ΔDNMT3B4</i> in primary lung cancer, suggesting a role of ΔDNMT3B in regulating promoter-specific methylation of common tumor suppressor genes in tumorigenesis. In this report, we provide first experimental evidence showing a direct involvement of ΔDNMT3B4 in regulating <i>RASSF1A</i> promoter methylation in human lung cancer cells. Knockdown of <i>ΔDNMT3B4</i> expression by small interfering RNA resulted in a rapid demethylation of <i>RASSF1A</i> promoter and reexpression of <i>RASSF1A</i> mRNA but had no effect on p16 promoter in the lung cancer cells. Conversely, normal bronchial epithelial cells with stably transfected <i>ΔDNMT3B4</i> gained an increased DNA methylation in <i>RASSF1A</i> promoter but not <i>p16</i> promoter. We conclude that promoter DNA methylation can be differentially regulated and ΔDNMT3Bs are involved in regulation of such promoter-specific <i>de novo</i> DNA methylation. [Cancer Res 2007;67(22):10647–52]</p></div>