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.