Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme.
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. Oncogene (2001) 20, 24 - 33.
Tsuji
T
T
Department of Oral Medicine and Diagnostic Sciences, Division of Oral Pathology, Harvard School of Dental Medicine, Boston, Massachusetts, MA 02115, USA.
Usui
S
S
Aida
T
T
Tachikawa
T
T
Hu
G F
GF
Sasaki
A
A
Matsumura
T
T
Todd
R
R
Wong
D T
DT
D000362:Agar; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D006224:Cricetinae; D003470:Culture Media; D019175:DNA Methylation; D003653:Decarboxylation; D018900:Dinucleotide Repeats / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D006131:Growth Inhibitors / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D007424:Intracellular Fluid / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009061:Mouth Mucosa / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D010641:Phenotype; D014176:Protein Biosynthesis; D011506:Proteins / Q000008:administration & dosage / Q000502:physiology*; D012436:S-Adenosylmethionine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003470:Culture Media; D006131:Growth Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D012436:S-Adenosylmethionine; D000362:Agar; D009955:Ornithine Decarboxylase