Methyl Donor Status Influences DNMT Expression and Global DNA Methylation in Cervical Cancer Cells

Poomipark, Natwadee; Flatley, Janet E; Hill, Marilyn H; Mangnall, Barbara; Azar, Elnaz; Grabowski, Peter; Powers, Hilary J

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저자정보: Poomipark, Natwadee (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield) Flatley, Janet E (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield) Hill, Marilyn H (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield) Mangnall, Barbara (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield) Azar, Elnaz (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield) Grabowski, Peter (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield) Powers, Hilary J (Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield)

저널정보: 아시아태평양암예방학회 Asian Pacific journal of cancer prevention : APJCP Asian Pacific journal of cancer prevention : APJCP 제17권 제7호

발행연도: 2016.1

수록면: 3,213 - 3,222 (10page)

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Background: Methyl donor status influences DNA stability and DNA methylation although little is known about effects on DNA methyltransferases. The aim of this study was to determine whether methyl-donor status influences DNA methyltransferase (Dnmt) gene expression in cervical cancer cells, and if so, whether there are associated effects on global DNA methylation. Materials and Methods: The human cervical cancer cell line, C4-II, was grown in complete medium and medium depleted of folate (F-M+) and folate and methionine (F-M-). Growth rate, intracellular folate, intracellular methionine and homocysteine in the extracellular medium were measured to validate the cancer cell model of methyl donor depletion. Dnmt expression was measured by qRT-PCR using relative quantification and global DNA methylation was measured using a flow cytometric method. Results: Intracellular folate and methionine concentrations were significantly reduced after growth in depleted media. Growth rate was also reduced in response to methyl donor depletion. Extracellular homocysteine was raised compared with controls, indicating disturbance to the methyl cycle. Combined folate and methionine depletion led to a significant down-regulation of Dnmt3a and Dnmt3b; this was associated with an 18% reduction in global DNA methylation compared with controls. Effects of folate and methionine depletion on Dnmt3a and 3b expression were reversed by transferring depleted cells to complete medium. Conclusions: Methyl donor status can evidently influence expression of Dnmts in cervical cancer cells, which is associated with DNA global hypomethylation. Effects on Dnmt expression are reversible, suggesting reversible modulating effects of dietary methyl donor intake on gene expression, which may be relevant for cancer progression.

#Cervical cancer #folate #methionine #DNA methylation #DNA methyltransferase

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