TY - JOUR
T1 - Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme
AU - Tsuji, Takanori
AU - Usui, Satomi
AU - Aida, Tadateru
AU - Tachikawa, Tetsuhiko
AU - Hu, Guo Fu
AU - Sasaki, Akira
AU - Matsumura, Tomohiro
AU - Todd, Randy
AU - Wong, David T.W.
N1 - Funding Information:
We would like to thank Dr Philip Cono for providing DFMO and his technical advice on ODC enzyme assay. We also thank Dr John LA Mitchell (Northern Illinois University) for providing the polyclonal antibody to ODC-Az detection, and Dr Keijiro Samejima for providing decarboxylated S-adenosylmethionine to HPLC analysis. This work was supported by Grants DE-12529 to T Tsuji, DE-12467 to DTW Wong, and DE-11983 to R Todd.
PY - 2001/1/4
Y1 - 2001/1/4
N2 - The hamster ornithine decarboxylase antizyme (ODC-Az) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1. Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial differentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a significant increase in demethylation of 5-methyl cytosines (m5C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase). We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development.
AB - The hamster ornithine decarboxylase antizyme (ODC-Az) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1. Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial differentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a significant increase in demethylation of 5-methyl cytosines (m5C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase). We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development.
KW - DNA demethylation
KW - Differentiation
KW - Hamster
KW - Oral cancer
KW - Ornithine decarboxylase antizyme
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U2 - 10.1038/sj.onc.1204051
DO - 10.1038/sj.onc.1204051
M3 - Article
C2 - 11244502
AN - SCOPUS:0035804216
SN - 0950-9232
VL - 20
SP - 24
EP - 33
JO - Oncogene
JF - Oncogene
IS - 1
ER -
