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

Yeonjoo Jung, Jinah Park, Tai Young Kim, Jung Hyun Park, Hyun Soon Jong, Seock Ah Im, Keith D. Robertson, Yung Jue Bang, Tae You Kim

Research output: Contribution to journalArticle

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1137-1148
Number of pages12
JournalJournal of Molecular Medicine
Volume85
Issue number10
DOIs
StatePublished - Oct 1 2007

    Fingerprint

Keywords

  • 5-aza-dC
  • DNA methyltransferase
  • Epigenetic gene silencing
  • Promoter hypermethylation
  • siRNAs

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Jung, Y., Park, J., Kim, T. Y., Park, J. H., Jong, H. S., Im, S. A., Robertson, K. D., Bang, Y. J., & Kim, T. Y. (2007). Potential advantages of DNA methyltransferase 1 (DNMT1)-targeted inhibition for cancer therapy. Journal of Molecular Medicine, 85(10), 1137-1148. https://doi.org/10.1007/s00109-007-0216-z