YTHDF1 promotes gastric carcinogenesis by controlling translation of FZD7

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here we aimed to investigate the role of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer (GC) tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of gastric cancer patients and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated GC cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyper-activation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.