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