Targeting novel m6A reader KHSRP impairs pancreatic ductal adenocarcinoma progression via attenuating FAK signaling

We report KH-type splicing regulatory protein (KHSRP) as a novel m6A reader with oncogenic functions in pancreatic ductal adenocarcinoma (PDAC). KHSRP recognizes and stabilizes its target mRNAs (e.g., MET, ITGAV and ITGB1) in an m6A-dependent manner, therefore activating downstream FAK signaling and promoting PDAC progression. Targeting KHSRP shows promising anti-tumoral effects in vitro and in vivo, indicating that KHSRP may serve as a therapeutic target for PDAC. Overall design: We performed m6A individual-nucleotide resolution cross-linking and immunoprecipitation sequencing (miCLIP-seq) and photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing (PAR-CLIP-seq) for KHSRP to investigate whether KHSRP possesses the characteristics of m6A-binding protein. To explore the underlying mechanism of KHSRP-mediated tumor progression, we conducted RNA sequencing (RNA-seq). We further performed mRNA stability analysis to examine the effect of KHSRP on mRNA lifetime.