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

Cited 58 time in Web of Science Cited 59 time in Scopus
Authors
Jung, Yeonjoo; Park, Jinah; Kim, Tai Young; Park, Jung-Hyun; Jong, Hyun-Soon; Im, Seock-Ah; Robertson, Keith D; Bang, Yung-Jue; Kim, Tae-You
Issue Date
2007-06-16
Publisher
Springer Verlag
Citation
J Mol Med. 2007 Oct;85(10):1137-48. Epub 2007 Jun 15.
Keywords
Adenocarcinoma/*drug therapy/enzymologyAntimetabolites, Antineoplastic/pharmacologyAzacitidine/*analogs & derivatives/pharmacologyCell Line, Tumor/drug effectsCell Proliferation/drug effectsDNA (Cytosine-5-)-Methyltransferase/*antagonists & inhibitorsDNA Damage/drug effectsDNA Methylation/drug effectsEpigenesis, Genetic/drug effectsGene Expression Regulation, Neoplastic/drug effectsGene SilencingHumansRNA, Small Interfering/*administration & dosageStomach Neoplasms/*drug therapy/enzymologyTransfection
Abstract
The 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.
ISSN
0946-2716 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17571247

http://hdl.handle.net/10371/22880
DOI
https://doi.org/10.1007/s00109-007-0216-z
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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