Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells.
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.
Kuck
Dirk
D
Division of Epigenetics, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg BW 69120, Germany. d.kuck@dkfz-heidelberg.de
Caulfield
Thomas
T
Lyko
Frank
F
Medina-Franco
Jose L
JL
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
D000970:Antineoplastic Agents; D004248:DNA (Cytosine-5-)-Methyltransferases; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D000097584:DNA Methyltransferase 3B; C008638:nanaomycin A; D000095622:Benzoisochromanequinones