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 m⁶A 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 m⁶A 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 m⁶A 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 m⁶A modification. In GPX8-KO cells, m⁶A 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 m⁶A modification, thereby affecting the expression and function of downstream genes. This study highlights the possible significance of GPX8 and the corresponding m⁶A regulatory or regulated genes as novel targets for antioxidant intervention in cancer therapy.