YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7.

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.

• Authors: Jingnan Pi, Wen Wang, Ming Ji, Xiaoshuang Wang, Xueju Wei, Jing Jin, Tao Liu, Jiaqi Qiang, Zhihong Qi, Feng Li, Yue Liu, Yanni Ma, Yanmin Si, Yue Huo, Yufeng Gao, Yiying Chen, Lei Dong, Rui Su, Jianjun Chen, Shuan Rao, Ping Yi, Shuyang Yu, Fang Wang, Jia Yu
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 10 Pg. 2651-2665 (05 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 32788173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• CTNNB1 protein, human
• FZD7 protein, human
• Frizzled Receptors
• RNA-Binding Proteins
• YTHDF1 protein, human
• beta Catenin

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carcinogenesis (genetics, metabolism, pathology)
• Cell Proliferation
• DNA Methylation
• Frizzled Receptors (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Prognosis
• Protein Biosynthesis
• RNA-Binding Proteins (genetics, metabolism)
• Stomach Neoplasms (genetics, metabolism, pathology)
• Survival Rate
• Tumor Cells, Cultured
• Wnt Signaling Pathway
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)