YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of <i>FZD7</i>

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 m⁶A RNA-binding protein 1 (YTHDF1), a key regulator of m⁶A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m⁶A-associated genetic mutations that regulated gastric tumorigenesis. <i>YTHDF1</i> was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of <i>YTHDF1</i> attenuated gastric cancer cell proliferation and tumorigenesis <i>in vitro</i> and <i>in vivo</i>. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (<i>FZD7</i>) in an m⁶A-dependent manner, and mutated <i>YTHDF1</i> enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of <i>YTHDF1</i> 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. SIGNIFICANCE: This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2651/F1.large.jpg.