N6-methyladenosine-enhanced FZR1 translation contributes to gemcitabine insensitivity in pancreatic cancer via quiescence maintenance [m6A-seq]

Herein, by detecting the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified the key role of hyper-m6A modification of the master G0/G1 regulator Fizzy and Cell Division Cycle 20 Related 1 (FZR1) in regulating gemcitabine sensitivity. Targeting m6A modification of FZR1 improves the gemcitabine treatment response of gemcitabine-insensitive PDAC cells in vitro and in vivo. Mechanistically, Gem Nuclear Organelle Associated Protein 5 (GEMIN5) was identified as a novel m6A mediator that specifically binds to m6A-modified FZR1 and recruits the eIF3 translation initiation complex to accelerate FZR1 translation. Upregulation of FZR1 maintains the G0/G1 quiescent state and impairs gemcitabine sensitivity of PDAC cells. Further clinical analysis showed that both high levels of FZR1 m6A modification and FZR1 protein indicated a poor response to gemcitabine. m6A-seq data for six PDAC cell lines and GEMIN5 PAR-CLIP-seq of PANC-1