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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Divisions of 1 Epigenetics, 2 Molecular Toxicology, and 3 Molecular Biophysics, Deutsches Krebsforschungszentrum, Heidelberg, Germany; 4 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
Requests for reprints: Frank Lyko, Division of Epigenetics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Phone: 49-6221-42-3800; Fax: 49-6221-42-3802; E-mail: f.lyko{at}dkfz.de.
DNA methylation regulates gene expression in normal and malignant cells. The possibility to reactivate epigenetically silenced genes has generated considerable interest in the development of DNA methyltransferase inhibitors. Here, we provide a detailed characterization of RG108, a novel small molecule that effectively blocked DNA methyltransferases in vitro and did not cause covalent enzyme trapping in human cell lines. Incubation of cells with low micromolar concentrations of the compound resulted in significant demethylation of genomic DNA without any detectable toxicity. Intriguingly, RG108 caused demethylation and reactivation of tumor suppressor genes, but it did not affect the methylation of centromeric satellite sequences. These results establish RG108 as a DNA methyltransferase inhibitor with fundamentally novel characteristics that will be particularly useful for the experimental modulation of epigenetic gene regulation.
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B. Brueckner, C. Stresemann, R. Kuner, C. Mund, T. Musch, M. Meister, H. Sultmann, and F. Lyko The Human let-7a-3 Locus Contains an Epigenetically Regulated MicroRNA Gene with Oncogenic Function Cancer Res., February 15, 2007; 67(4): 1419 - 1423. [Abstract] [Full Text] [PDF] |
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C. Stresemann, B. Brueckner, T. Musch, H. Stopper, and F. Lyko Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res., March 1, 2006; 66(5): 2794 - 2800. [Abstract] [Full Text] [PDF] |
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A. Rouhi, L. Gagnier, F. Takei, and D. L. Mager Evidence for epigenetic maintenance of Ly49A monoallelic gene expression. J. Immunol., March 1, 2006; 176(5): 2991 - 2999. [Abstract] [Full Text] [PDF] |
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F. Lyko and R. Brown DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies J Natl Cancer Inst, October 19, 2005; 97(20): 1498 - 1506. [Abstract] [Full Text] [PDF] |
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