title: Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells.
abstract: Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes.
authors.affiliation: Division of Epigenetics, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg BW 69120, Germany. d.kuck@dkfz-heidelberg.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuck
authors.forename: Thomas
authors.initials: T
authors.lastname: Caulfield
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.forename: Jose L
authors.initials: JL
authors.lastname: Medina-Franco
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D045325:HCT116 Cells; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D009285:Naphthoquinones / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D000097584:DNA Methyltransferase 3B; D000095622:Benzoisochromanequinones
chemical_list: D000970:Antineoplastic Agents; D004248:DNA (Cytosine-5-)-Methyltransferases; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D000097584:DNA Methyltransferase 3B; C008638:nanaomycin A; D000095622:Benzoisochromanequinones