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

TL;DR

Zinc ions reduce DNA methylation and cancer cell aggression in esophageal cancer, suggesting a potential new treatment approach.

Contribution

Zn2+ was shown to inhibit ESCC malignancy via DNA demethylation and enhance cisplatin efficacy.

Findings

Zn2+ treatment reduced CpG methylation in promoter regions of ESCC and control cells.

Zn2+ increased RNA expression of MT1E, MT1H, and MT1X genes by decreasing their DNA methylation.

Zn2+ combined with cisplatin showed greater inhibition of ESCC cells than cisplatin alone.

Abstract

Abnormalities in trace elements and the incidence of oesophageal squamous cell carcinoma (ESCC) have been reported in China. Zinc ions (Zn2+) are known to regulate DNA methylation by stabilizing methylase activity. However, the relationship between DNA methylation and Zn2+ dysregulation in ESCC cells remains unclear. In this study, we examined changes in the biological behavior of ESCC cells treated with or without Zn2+.

Biological behaviour changes in ESCC cells treated with or without Zn2+ were analysed. Differences in the methylome and transcriptome of Zn2+-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 Zn2+.

Zn2+ can inhibit the malignant biological behaviour of ESCC cells. CpG methylation levels of promoter regions were decreased after Zn2+ 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 Zn2+ treatment. Zn2+ may enhance the expression of metallothioneins (MTs) via positive feedback through methylation regulation mechanisms. In vitro assays showed that the IC50 of Zn2+ 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.

Zn2+ can reduce the methylation level and malignant biological behaviour of ESCC cells. The combination of Zn2+ and cisplatin increases ESCC inhibition. Further study of MTs as biomarkers and targets in ESCC is warranted.

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