m 6 A demethylation of FOSL1 mRNA protects hepatoma cells against necrosis under glucose deprivation.

Stress-adaptive mechanisms enabling cancer cells to survive under glucose deprivation remain elusive. N 6 -methyladenosine (m 6 A) modification plays important roles in determining cancer cell fate and cellular stress response to nutrient deficiency. However, whether m 6 A modification functions in the regulation of cancer cell survival under glucose deprivation is unknown. Here, we found that glucose deprivation reduced m 6 A modification levels. Increasing m 6 A modification resulted in increased hepatoma cell necrosis under glucose deprivation, whereas decreasing m 6 A modification had an opposite effect. Integrated m 6 A-seq and RNA-seq revealed potential targets of m 6 A modification under glucose deprivation, including the transcription factor FOSL1; further, glucose deprivation upregulated FOSL1 by inhibiting FOSL1 mRNA decay in an m 6 A-YTHDF2-dependent manner through reducing m 6 A modification in its exon1 and 5'-UTR regions. Functionally, FOSL1 protected hepatoma cells against glucose deprivation-induced necrosis in vitro and in vivo. Mechanistically, FOSL1 transcriptionally repressed ATF3 by binding to its promoter. Meanwhile, ATF3 and MAFF interacted via their leucine zipper domains to form a heterodimer, which competed with NRF2 for binding to antioxidant response elements in the promoters of NRF2 target genes, thereby inhibiting their transcription. Consequently, FOSL1 reduced the formation of the ATF3-MAFF heterodimer, thereby enhancing NRF2 transcriptional activity and the antioxidant capacity of glucose-deprived-hepatoma cells. Thus, FOSL1 alleviated the necrosis-inducing effect of glucose deprivation-induced reactive oxygen species accumulation. Collectively, our study uncovers the protective role of m 6 A-FOSL1-ATF3 axis in hepatoma cell necrosis under glucose deprivation, and may provide new targets for cancer therapy.