FTO-mediated autophagy inhibition promotes non-small cell lung cancer progression by reducing SESN2 mRNA stability [MeRIP-Seq]

N6-methyladenosine (m6A) serves as the most abundant mRNA modification within eukaryotes that is involved in autophagy and progression of non-small cell lung cancer (NSCLC). The role of the m6A demethylase FTO in NSCLC progression has recently received widespread attention. However, the mechanism of FTO-mediated autophagy regulation in NSCLC progression is unclear. In this study, we found that FTO was significantly up-regulated in NSCLC, and down-regulation of FTO blocked the growth, invasion and migration of NSCLC cells via autophagy induction. Importantly, SESN2 was involved in m6A regulation during autophagy in NSCLC cells. FTO deficiency prompted IGF2BP1 to interact with SESN2 mRNA, which led to an increase in SESN2 mRNA stability as well as enhanced SESN2 protein levels. However, FTO inhibited autophagic flux via down-regulation of SESN2, thereby promoting the growth, invasion and migration of NSCLC cells. Our findings uncovered that FTO-mediated autophagy inhibition promotes malignant progression of NSCLC via reduction of SESN2 mRNA stability, thus providing novel notions for the prevention and treatment of NSCLC. Overall design: To investigate autophagy-mediated alterations in m6A modification of specific genes, we performed MeRIP-seq and RNA-seq analyses with autophagy-activated H460 cells treated with rapamycin for 24h. Then, the data obtained from RNA-seq or MeRIP-seq was used to perform differentially gene or differentially methylated gene expression profiling analysis. Thereafter, the two datasets were overlaid with pre-existing autophagy-associated genes to obtain key common genes for subsequent experiments.