TY - JOUR
T1 - Potential advantages of DNA methyltransferase 1 (DNMT1)-targeted inhibition for cancer therapy
AU - Jung, Yeonjoo
AU - Park, Jinah
AU - Kim, Tai Young
AU - Park, Jung Hyun
AU - Jong, Hyun Soon
AU - Im, Seock Ah
AU - Robertson, Keith D.
AU - Bang, Yung Jue
AU - Kim, Tae You
N1 - Funding Information:
Acknowledgments This work was supported in part by grants from the Korean Ministry of Science and Technology through the National Research Laboratory Program for Cancer Epigenetics (No. M10400000336-06J0000-33610), and BK21 Project for Medicine, Dentistry and Pharmacy.
PY - 2007/10
Y1 - 2007/10
N2 - 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.
AB - 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.
KW - 5-aza-dC
KW - DNA methyltransferase
KW - Epigenetic gene silencing
KW - Promoter hypermethylation
KW - siRNAs
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U2 - 10.1007/s00109-007-0216-z
DO - 10.1007/s00109-007-0216-z
M3 - Article
C2 - 17571247
AN - SCOPUS:34748835339
SN - 0946-2716
VL - 85
SP - 1137
EP - 1148
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 10
ER -