TY - JOUR
T1 - Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells
AU - Kuck, Dirk
AU - Caulfield, Thomas
AU - Lyko, Frank
AU - Medina-Franco, Jose L.
PY - 2010/11
Y1 - 2010/11
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=78649676706&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-10-0609
DO - 10.1158/1535-7163.MCT-10-0609
M3 - Article
C2 - 20833755
AN - SCOPUS:78649676706
SN - 1535-7163
VL - 9
SP - 3015
EP - 3023
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 11
ER -