YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7
YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7
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YTHDF1通过控制FZD7的翻译促进胃癌发生
DOI：
10.1158/0008-5472.can-20-0066
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发表时间：
2021-05-15
期刊：
影响因子：
11.2
通讯作者：
Yu, Jia
中科院分区：
文献类型：
--
作者：
Pi, Jingnan;Wang, Wen;Yu, Jia
N-6-甲基腺苷（m（6）A）是哺乳动物中最普遍的内部RNA修饰，可调节修饰的RNA转录物的稳态和功能。在此，我们旨在研究YTH m（6）A RNA结合蛋白1（YTHDF 1）在胃癌发生中的作用，YTHDF 1是m（6）A甲基化的关键调节因子。对不同人类癌症数据库的多项生物信息学分析确定了调节胃肿瘤发生的关键m（6）A相关基因突变。YTHDF 1在约7%的胃癌患者中发生突变，YTHDF 1的高表达与更具侵袭性的肿瘤进展和较差的总生存率相关。抑制YTHDF 1在体外和体内减弱胃癌细胞增殖和肿瘤发生。在机制上，YTHDF 1以m（6）A依赖的方式促进关键Wnt受体frizzled 7（FZD 7）的翻译，并且突变的YTHDF 1增强FZD 7的表达，导致Wnt/β-连环蛋白途径的过度激活和促进胃癌发生。我们的研究结果证明了YTHDF 1的致癌作用及其m（6）A介导的Wnt/beta-catenin信号转导在胃癌中的调节作用，提供了一种靶向这种表观遗传调节因子的新方法，在这种疾病中，意义：这项研究提供了一个基本原理，通过操纵表观遗传调节因子来控制癌症中关键致癌驱动因子的翻译，代表了一种新的有效的抗癌治疗策略。[图形]。
N-6-methyladenosine (m(6)A) 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 m(6)A RNA-binding protein 1 (YTHDF1), a key regulator of m(6)A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m(6)A-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 m(6)A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/beta-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m(6)A-mediated regulation of Wnt/beta-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.[GRAPHICS].