A Study on the Effect of Vitamins A and C to Modulate the Expression of NKG2D Ligands in Hepatic and Colon Cancer Cells

Abstract

Recently, vitamins have been shown to act as epigenetic modifier. Cancer cells exhibit transcriptional downregulation of NK group 2D ligands (NKG2DLs) through repressive methylation and are largely resistant to NK cell-mediated eradication. We herein investigated the potential of recently reported epigenome modifying vitamins A, C, and E in inducing the expression of epigenetically silenced NKG2DLs in cancer cells. Based on the cell viability assay three concentrations, i.e., 25, 50, and 100 µg/ml of all vitamins were selected for treatment. Results showed that treatment of both vitamin A and C significantly upregulates expression of two major NKG2DLs namely MICA and MICB. Simultaneously, both, vitamin A and C significantly reduces the methylation process by downregulating DNA methyltransferases (DNMTs) expression level. Vitamin C, but not vitamin A, significantly upregulates TETs (DNA demethylases) expression. Further, we assessed the impact of both vitamins A and C on S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio levels and found no significant changes in SAM/SAH ratio. Overall, we clearly found that both vitamin A and C induces NKG2DLs mostly through repressing the expression of DNMTs, suggesting their potential role in improving the targeting of tumor cells by promoting the engagement and clearance of tumor cells with NK cells.

Authors’ Contributions

MAZ, MN, MIK, and HC: concept and design of the work; MAZ, MN: data collection; MN, MAZ, and MIK: data analysis and interpretation; MN and MIK: drafting the article; HC, MIK, and MAZ: critical revision of the article; HC, MIK, MAZ, and MN: final approval.

Conflict of Interest Statement

All the authors agree with the content of the manuscript and do not have any potential conflict of interest regarding the work and manuscript.

Additional information

Funding

This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant no. (G-464-130-1440). The authors, therefore, acknowledge with thanks to DSR technical and financial support.