YTHDF1 promotes radio-resistance and regulates the repair of DNA double-strand breaks in ESCC

Abstract The morbidity and mortality of esophageal carcinoma (ESCA) patients is high in China for which radical radiotherapy remains the frontline treatment. Radio-resistant patients show high rates of relapse and poor overall survival (OS). In this study, we report high YTHDF1 expression in ESCA patients that is associated with radio-resistance and poor OS. Accordingly, YTHDF1 silencing improved the radio-sensitivity of ESCC cells. Bioinformatics, m6A sequencing, KEGG and GO analysis, and m6A-IP-qPCR validations revealed a positive correlation between AURKA and YTHDF1. AURKA was subsequently found to positively regulate NHEJ promoting radio-resistance. From these data, we speculate that YTHDF1 binds to AURKA to upregulate NHEJ, promoting radio-resistance. Clinical specimens were collected and the role of YTHDF1 and AURKA during radio-resistance in vivo were investigated. These data reveal new predictors of radiotherapy efficacy and highlight novel and effective interventions to reverse radio-resistance.