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Background  DNA hypermethylation of tumor suppressor genes is observed in precancerous lesions and oral cancer of individuals with the habits of betel quid (BQ) chewing.  SIRT1  has been identified as playing a role in the maintenance of epithelial integrity, and its alteration is often related to carcinogenesis. However, the methylation and transcription status of  SIRT1  in patients with BQ chewing-related oral cancer has not been investigated. We examined the methylation status of  SIRT1  in paraffin-embedded tissue samples of oral squamous cell carcinoma (OSCC) obtained from BQ chewing and non-chewing patients and in tissue samples from healthy control subjects. In addition, we examined whether the hypermethylation of  SIRT1  followed by its transcriptional downregulation in the human gingival epithelial cells could be caused by arecoline, a major component of BQ. Furthermore, we investigated the methylation status of  SIRT1  in smear samples of macroscopically healthy buccal mucosa from subjects with a habit of BQ chewing.    Results   SIRT1  was significantly hypermethylated in tissue samples of OSCC from BQ chewers and non-chewers than in oral mucosa from healthy control subjects. Results also showed that the hypermethylation level of  SIRT1  was significantly higher in OSCC of patients with BQ chewing habits than in those of non-chewing habits ( p  < 0.05). Our in vitro model showed that hypermethylation is followed by downregulation of the transcriptional level of  SIRT1  ( p  < 0.05). The methylation levels of  SIRT1  in the smear samples obtained from BQ chewing individuals were significantly higher than those in the samples obtained from individuals that did not chew BQ. The duration of BQ chewing habits was correlated positively to the frequency of  SIRT1  hypermethylation ( p  < 0.05).    Conclusions  Our results suggest that DNA hypermethylation of  SIRT1  is involved in the occurrence of oral cancer in BQ chewing patients and that hypermethylation in the oral mucosa of BQ chewers could be a predictive marker for the occurrence of malignant transformation. This is the first report that showed DNA hypermethylation in clinically healthy oral epithelium of BQ chewers. Our study shows evidence that DNA hypermethylation may be an early event of oral carcinogenesis prior to observable clinical changes.

DNA hypermethylation of sirtuin 1 (SIRT1) caused by betel quid chewing—a possible predictive biomarker for malignant transformation