Anticancer effects of zinc ion-mediated DNA demethylation in oesophageal squamous cell carcinoma.

BACKGROUND: Abnormalities in trace elements and the incidence of oesophageal squamous cell carcinoma (ESCC) have been reported in China. Zinc ions (Zn(2+)) are known to regulate DNA methylation by stabilizing methylase activity. However, the relationship between DNA methylation and Zn(2+) dysregulation in ESCC cells remains unclear. In this study, we examined changes in the biological behavior of ESCC cells treated with or without Zn(2+). METHODS: Biological behaviour changes in ESCC cells treated with or without Zn(2+) were analysed. Differences in the methylome and transcriptome of Zn(2+)-treated cells were determined by reduced representation bisulfite sequencing and RNA sequencing. An MTT cell viability assay was used to evaluate the cytotoxicity of cisplatin combined with Zn(2+). RESULTS: Zn(2+) can inhibit the malignant biological behaviour of ESCC cells. CpG methylation levels of promoter regions were decreased after Zn(2+) treatment in both ESCC and control cells. The degree of DNA methylation of genes encoding the metal ion-binding factors MT1E, MT1H and MT1X was significantly decreased, but their RNA expression levels were significantly increased after Zn(2+) treatment. Zn(2+) may enhance the expression of metallothioneins (MTs) via positive feedback through methylation regulation mechanisms. In vitro assays showed that the IC50 of Zn(2+) in ESCC cells was significantly lower than that in cells treated with cisplatin alone. In addition, ECa patients with high MT1E expression had a better prognosis. CONCLUSION: Zn(2+) can reduce the methylation level and malignant biological behaviour of ESCC cells. The combination of Zn(2+) and cisplatin increases ESCC inhibition. Further study of MTs as biomarkers and targets in ESCC is warranted.