Abstract
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. YTHDF1 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 YTHDF1 attenuated gastric cancer 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 hyperactivation 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. 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.
Highlights
More than 100 distinct RNA modifications have been characterized in the last few decades, among which, the N6-methyladenosine (m6A) modification is the most abundant form in eukaryotic mRNA [1]
YTHDF1 Gene amplifications in gastric cancer To interrogate the genetic alterations of m6A-associated genes involved in gastric cancer development, cBioPortal datasets including 630 primary gastric adenocarcinomas were analyzed
These results reveal that YTHDF1 can activate the Wnt/b-catenin pathway in gastric cancer cells, which is mediated by translational control of FZD7, a key receptor in Wnt/b-catenin signaling
Summary
More than 100 distinct RNA modifications have been characterized in the last few decades, among which, the N6-methyladenosine (m6A) modification is the most abundant form in eukaryotic mRNA [1]. The reversible nature of m6A modification was recognized because of the discovery of two RNA m6A demethylases, a-ketoglutarate–dependent dioxygenase FTO and alkB homologue 5 It is known that m6A is incorporated into single-strand RNA molecules by a multicomponent methyltransferase complex containing METTL3, METTL14, and WTAP [10]. Structured RNA can be modified by another m6A methyltransferase, METTL16 [11, 12]. The majority of YTH (YTHDF1-3 and YTHDC2) and IGF2BP (IGF2BP13) family proteins bind to m6A-modified mRNAs and regulate their stability and translation [13,14,15,16,17]. Other proteins can bind m6A-modified precursor RNAs in the nucleus and affect their processing [1, 18, 19].
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