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

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Abstract

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.

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Most cited references 33

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Cigarette smoking and DNA methylation

Ken Lee, Zdenka Pausova (2013)

DNA methylation is the most studied epigenetic modification, capable of controlling gene expression in the contexts of normal traits or diseases. It is highly dynamic during early embryogenesis and remains relatively stable throughout life, and such patterns are intricately related to human development. DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors. Genetic variants at a specific locus can influence both regional and distant DNA methylation. The environment can have varying effects on DNA methylation depending on when the exposure occurs, such as during prenatal life or during adulthood. In particular, cigarette smoking in the context of both current smoking and prenatal exposure is a strong modifier of DNA methylation. Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases. As such, DNA methylation is a potential mechanistic link between current smoking and cancer, as well as prenatal cigarette-smoke exposure and the development of adult chronic diseases.

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Quantitation of the cellular content of saliva and buccal swab samples

Christiane Theda, Seo Hwang, Anna Czajko … (2018)

Buccal swabs and saliva are the two most common oral sampling methods used for medical research. Often, these samples are used interchangeably, despite previous evidence that both contain buccal cells and blood leukocytes in different proportions. For some research, such as epigenetic studies, the cell types contributing to the analysis are highly relevant. We collected such samples from twelve children and twenty adults and, using Papanicolaou staining, measured the proportions of epithelial cells and leukocytes through microscopy. To our knowledge, no studies have compared cellular heterogeneity in buccal swab and saliva samples from adults and children. We confirmed that buccal swabs contained a higher proportion of epithelial cells than saliva and that children have a greater proportion of such cells in saliva compared to adults. At this level of resolution, buccal swabs and saliva contained similar epithelial cell subtypes. Gingivitis in children was associated with a higher proportion of leukocytes in saliva samples but not in buccal swabs. Compared to more detailed and costly methods such as flow cytometry or deconvolution methods used in epigenomic analysis, the procedure described here can serve as a simple and low-cost method to characterize buccal and saliva samples. Microscopy provides a low-cost tool to alert researchers to the presence of oral inflammation which may affect a subset of their samples. This knowledge might be highly relevant to their specific research questions, may assist with sample selection and thus might be crucial information despite the ability of data deconvolution methods to correct for cellular heterogeneity.

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Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis.

A Smet, Lingeng Lu, Herbert Yu … (2007)

MicroRNAs (miRNA) are endogenous noncoding small RNAs that regulate the activity of mRNAs. Many miRNA genes, including let-7a-3, are located in CpG islands, suggesting possible epigenetic regulation of their expression. Promoter CpG island methylation of tumor suppressor genes is involved in cancer development and progression. Using real-time methylation-specific PCR and real-time reverse transcription-PCR, we analyzed DNA methylation in the let-7a-3 gene and miRNA expression of let-7a in 214 patients with epithelial ovarian cancer to assess the effect of let-7a-3 methylation on the expressions of let-7a as well as a possible target of let-7 regulation, insulin-like growth factor-II (IGF-II). The association of let-7a-3 methylation with patient survival outcomes was also evaluated. let-7a-3 methylation was detected in epithelial ovarian cancer, and the expression of let-7a was slightly affected by the methylation, but the effect was not substantial. The methylation of let-7a-3, however, was inversely correlated with IGF-II expression and positively with insulin-like growth factor binding protein-3 (IGFBP-3) expression. Patients with methylated let-7a-3 seemed to have reduced risk for death compared with those without, and the association was independent of patient age at surgery, tumor grade, disease stage, and IGF-II or IGFBP-3 expression. No association was found for let-7a-3 methylation and disease progression. These results suggest that the let-7a-3 gene is methylated and the methylation may affect IGF-II expression and the survival of ovarian cancer patients. Further investigation of the role of miRNAs and their regulation in cancer is warranted.

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Author and article information

Contributors

Yoshihiro Abiko:

ORCID: http://orcid.org/0000-0001-6358-8508

yoshi-ab@hoku-iryo-u.ac.jp

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 13 January 2020

Publication date PMC-release: 13 January 2020

Publication date Collection: 2020

Volume: 12

Electronic Location Identifier: 12

Affiliations

[1 ]ISNI 0000 0004 1769 5590, GRID grid.412021.4, Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, , Health Sciences University of Hokkaido, ; Hokkaido, 061-0293 Japan

[2 ]ISNI 0000 0004 1769 5590, GRID grid.412021.4, Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, , Health Sciences University of Hokkaido, ; Hokkaido, 061-0293 Japan

[3 ]ISNI 0000 0004 1769 5590, GRID grid.412021.4, Research Institute of Cancer Prevention, , Health Sciences University of Hokkaido, ; Hokkaido, 061-0293 Japan

[4 ]ISNI 0000 0000 9949 4354, GRID grid.412816.8, Department of General Education, School of Dental Medicine, , Tsurumi University, ; Kanagawa, 230-8501 Japan

[5 ]ISNI 0000 0000 9949 4354, GRID grid.412816.8, Department of Pathology, School of Dental Medicine, , Tsurumi University, ; Kanagawa, 230-8501 Japan

[6 ]Department of Oral and Maxillofacial Surgery, Army Hospital, Colombo, Sri Lanka

[7 ]ISNI 0000 0004 1769 5590, GRID grid.412021.4, Division of Oral and Maxillofacial Surgery, Department of Human Biology and Pathophysiology, School of Dentistry, , Health Sciences University of Hokkaido, ; Hokkaido, 061-0293 Japan

Author information

Yoshihiro Abiko http://orcid.org/0000-0001-6358-8508

Article

Publisher ID: 806

DOI: 10.1186/s13148-019-0806-y

PMC ID: 6958620

PubMed ID: 31931863

SO-VID: 98300d20-3685-4e89-881e-b9f95e10920d

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 September 2019

Date accepted : 30 December 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science and Technology;

Award ID: 25305036

Award ID: 17K11916

Award Recipient : Hiroki Nagayasu Itsuo Chiba

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: oral cancer,sirtuin 1,betel quid chewing,arecoline,malignant transformation

Data availability:

ScienceOpen disciplines: Genetics

Keywords: oral cancer, sirtuin 1, betel quid chewing, arecoline, malignant transformation

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

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Most cited references 33

Cigarette smoking and DNA methylation

Quantitation of the cellular content of saliva and buccal swab samples

Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis.

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