GPX8 deficiency-induced oxidative stress reprogrammed m6A epitranscriptome of oral cancer cells

Glutathione peroxidase 8 (GPX8) is a key regulator of redox homoeostasis. Whether its antioxidant activity participates in the regulation of m(6)A modification is a crucial issue, which has important application value in cancer treatment. In this study, MeRIP-seq was used to explore the characteristics of transcriptome-wide m(6)A modification in GPX8-deficient oral cancer cells. Oxidative stress caused by the lack of GPX8 resulted in 1,279 hyper- and 2,287 hypo-methylated m(6)A peaks and 2,036 differentially expressed genes in GPX8-KO cells. Twenty-eight differentially expressed genes were related to the cell response to oxidative stress, and half of them changed their m(6)A modification. In GPX8-KO cells, m(6)A regulators IGF2BP2 and IGF2BP3 were upregulated, while FTO, RBM15, VIRMA, ZC3H13, and YTHDC2 were downregulated. After H2O2 treatment, the expression changes of RBM15, IGF2BP2, and IGF2BP3 were further enhanced. These data indicated that GPX8-mediated redox homoeostasis regulated m(6)A modification, thereby affecting the expression and function of downstream genes. This study highlights the possible significance of GPX8 and the corresponding m(6)A regulatory or regulated genes as novel targets for antioxidant intervention in cancer therapy.