m6A demethylase FTO induces NELL2 expression by inhibiting E2F1 m6A modification leading to metastasis of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) represents one of the primary causes of cancer-related mortality all over the world. Following our initial finding of the upregulated expression of E2F transcription factor-1 (E2F1) in the NSCLC-related microarray, this study aimed to explore the regulatory role of E2F1 and underlying mechanism in NSCLC development. NSCLC cell viability, migration, and invasion were evaluated utilizing Cell Counting Kit 8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), wound-healing, and Transwell assays. Loss- and gain-function assays were performed to determine the effects of the fat mass and obesity-associated protein (FTO)/E2F1/neural epidermal growth factor-like 2 (NELL2) axis on NSCLC cell behaviors in vitro and NSCLC tumor growth in vivo. E2F1 was highly expressed in both NSCLC tissues and cells. E2F1 augmented the viability, migration, and invasion of NSCLC cells, which was attributable to E2F1 transcriptionally activating NELL2. FTO upregulated the expression of E2F1 by inhibiting the m6A modification of E2F1. The FTO/E2F1/NELL2 axis modulated NSCLC cell viability, migration, and invasion in vitro as well as affected NSCLC tumor growth and metastasis in vivo. The FTO/E2F1/NELL2 axis may impart pro-tumorigenic effects on the cell behavior of NSCLC cells and thus accelerate NSCLC progression.