GPX8 deficiency–induced oxidative stress reprogrammed m6A epitranscriptome of oral cancer cells
Xun Chen, Lingyu Yuan, Lejia Zhang, Liutao Chen, Yi He, Chao Wang, Jie Wu, Shangwu Chen, Wei Zhao, Dongsheng Yu
Abstract
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.