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Potential advantages of DNA methyltransferase 1 (DNMT1)-targeted inhibition for cancer therapy

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dc.contributor.authorJung, Yeonjoo-
dc.contributor.authorPark, Jinah-
dc.contributor.authorKim, Tai Young-
dc.contributor.authorPark, Jung-Hyun-
dc.contributor.authorJong, Hyun-Soon-
dc.contributor.authorIm, Seock-Ah-
dc.contributor.authorRobertson, Keith D-
dc.contributor.authorBang, Yung-Jue-
dc.contributor.authorKim, Tae-You-
dc.date.accessioned2009-12-28T12:57:01Z-
dc.date.available2009-12-28T12:57:01Z-
dc.date.issued2007-06-16-
dc.identifier.citationJ Mol Med. 2007 Oct;85(10):1137-48. Epub 2007 Jun 15.en
dc.identifier.issn0946-2716 (Print)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17571247-
dc.identifier.urihttps://hdl.handle.net/10371/22880-
dc.description.abstractThe deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) has been used as a drug in a part of cancer therapy. However, because of its incorporation into DNA during DNA synthesis, 5-aza-dC can cause DNA damage, mutagenesis, and cytotoxicity. In view of the adverse effects of 5-aza-dC, DNMT-targeted inhibition may be a more effective approach than treatment with 5-aza-dC. To address the possibility of DNMT-targeted cancer therapy, we compared the effects of treatment with small interfering ribonucleic acids (siRNAs) specific for DNMT1 or DNMT3b and treatment with 5-aza-dC on transcription, cell growth, and DNA damage in gastric cancer cells. We found that DNMT1-targeted inhibition induced the re-expression and reversed DNA methylation of five (CDKN2A, RASSF1A, HTLF, RUNX3, and AKAP12B) out of seven genes examined, and 5-aza-dC reactivated and demethylated all seven genes. In contrast, DNMT3b siRNAs did not show any effect. Furthermore, the double knockdown of DNMT1 and DNMT3b did not show a synergistic effect on gene re-expression and demethylation. In addition, DNMT1 siRNAs showed an inhibitory effect of cell proliferation in the cancer cells and the induction of cell death without evidence of DNA damage, whereas treatment with 5-aza-dC caused DNA damage as demonstrated by the comet assay. These results provide a rationale for the development of a DNMT1-targeted strategy as an effective epigenetic cancer therapy.en
dc.language.isoenen
dc.publisherSpringer Verlagen
dc.subjectAdenocarcinoma/*drug therapy/enzymologyen
dc.subjectAntimetabolites, Antineoplastic/pharmacologyen
dc.subjectAzacitidine/*analogs & derivatives/pharmacologyen
dc.subjectCell Line, Tumor/drug effectsen
dc.subjectCell Proliferation/drug effectsen
dc.subjectDNA (Cytosine-5-)-Methyltransferase/*antagonists & inhibitorsen
dc.subjectDNA Damage/drug effectsen
dc.subjectDNA Methylation/drug effectsen
dc.subjectEpigenesis, Genetic/drug effectsen
dc.subjectGene Expression Regulation, Neoplastic/drug effectsen
dc.subjectGene Silencingen
dc.subjectHumansen
dc.subjectRNA, Small Interfering/*administration & dosageen
dc.subjectStomach Neoplasms/*drug therapy/enzymologyen
dc.subjectTransfectionen
dc.titlePotential advantages of DNA methyltransferase 1 (DNMT1)-targeted inhibition for cancer therapyen
dc.typeArticleen
dc.contributor.AlternativeAuthor정연주-
dc.contributor.AlternativeAuthor박진아-
dc.contributor.AlternativeAuthor김태영-
dc.contributor.AlternativeAuthor박정현-
dc.contributor.AlternativeAuthor종현순-
dc.contributor.AlternativeAuthor임석아-
dc.contributor.AlternativeAuthor박영주-
dc.contributor.AlternativeAuthor김태유-
dc.identifier.doi10.1007/s00109-007-0216-z-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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