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DNMT3B Variants Regulate DNA Methylation in a Promoter-Specific Manner

Departments of ¹ Thoracic/Head and Neck Medical Oncology and ² Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ³ Department of Oncology, Beijing Cancer Hospital, Beijing University School of Oncology, Beijing, China

Requests for reprints: Li Mao, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Box 437, Unit 432, Room FC9.3065, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: lmao{at}mdanderson.org.

DNA methyltransferase 3B (DNMT3B) is critical in de novo DNA methylation during development and tumorigenesis. We recently reported the identification of a DNMT3B subfamily, DNMT3B, which contains at least seven variants, resulting from alternative pre-mRNA splicing. DNMT3Bs are the predominant expression forms of DNMT3B in human lung cancer. A strong correlation was observed between the promoter methylation of RASSF1A gene but not p16 gene (both frequently inactivated by promoter methylation in lung cancer) and expression of DNMT3B4 in primary lung cancer, suggesting a role of DNMT3B 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 DNMT3B4 in regulating RASSF1A promoter methylation in human lung cancer cells. Knockdown of DNMT3B4 expression by small interfering RNA resulted in a rapid demethylation of RASSF1A promoter and reexpression of RASSF1A mRNA but had no effect on p16 promoter in the lung cancer cells. Conversely, normal bronchial epithelial cells with stably transfected DNMT3B4 gained an increased DNA methylation in RASSF1A promoter but not p16 promoter. We conclude that promoter DNA methylation can be differentially regulated and DNMT3Bs are involved in regulation of such promoter-specific de novo DNA methylation. [Cancer Res 2007;67(22):10647–52]

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