Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells

Dirk Kuck, Thomas Caulfield, Frank Lyko, Jose L. Medina-Franco

Research output: Contribution to journalArticle

106 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3015-3023
Number of pages9
JournalMolecular cancer therapeutics
Volume9
Issue number11
DOIs
StatePublished - Nov 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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