MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-10, Vol.104 (40), p.15805-15810
• Main Authors: Fabbri, Muller, Garzon, Ramiro, Cimmino, Amelia, Liu, Zhongfa, Zanesi, Nicola, Callegari, Elisa, Liu, Shujun, Alder, Hansjuerg, Costinean, Stefan, Fernandez-Cymering, Cecilia, Volinia, Stefano, Guler, Gulnur, Morrison, Carl D, Chan, Kenneth K, Marcucci, Guido, Calin, George A, Huebner, Kay, Croce, Carlo M
• Format: Article
• Language: English
• Subjects: Biological Sciences; Carcinogenesis; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Cell lines; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; DNA Methyltransferase 3A; DNA Methyltransferase 3B; DNA, Neoplasm - genetics; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genes; Humans; Lung - enzymology; Lung cancer; Lung neoplasms; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Messenger RNA; Methylation; MicroRNA; MicroRNAs - genetics; Oligonucleotides; Oncology; Prognosis; Ribonucleic acid; RNA; RNA, Neoplasm - genetics; Survival Analysis; Transfection; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0707628104

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes. Recent studies suggest roles of miRNAs in carcinogenesis. We and others have shown that expression profiles of miRNAs are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 3'-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated in lung cancer and associated with poor prognosis. We investigated whether miR-29s could target DNMT3A and -B and whether restoration of miR-29s could normalize aberrant patterns of methylation in non-small-cell lung cancer. Here we show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer tissues, and that miR-29s directly target both DNMT3A and -3B. The enforced expression of miR-29s in lung cancer cell lines restores normal patterns of DNA methylation, induces reexpression of methylation-silenced tumor suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro and in vivo. These findings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer.