The present study was designed to investigate the potential relationship between CDKN2A (p16) gene hypermethylation, which has reported to be frequently observed in oral squamous cell carcinomas (OSCCs), and expression of human DNA methyltransferases (DNMTs: DNMT1, DNMT3A and DNMT3B). Twenty-five pairs of primary OSCCs and matched normal oral mucosa tissues were examined. The p16 gene was hypermethylated (48%) in the tumors showing significant down-regulation of both mRNA and protein expressions. A demethylation assay on 8 OSCC-derived cell lines was also performed by means of treatment with the demethylating agent, 5-aza-2'-deoxycytidine. Four of 5 cell lines showing down-regulation of the p16 gene, revealed re-activation of gene expression after the treatment. In contrast, frequent over-expression of DNMT mRNA expression, also found in the expression of the proteins, was detected: DNMT1 at 72% and DNMT3A at 56%, and DNMT3B at 64%, respectively. However, we could not identify any statistical significance between p16-hypermethylation status in individual tumors and the expression of any of the three DNMTs. These data suggest that hypermethylation of the p16 gene and up-regulation of DNMTs are involved in oral carcinogenesis, but they may be through different mechanisms.

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