2. Academic Validation
  3. YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7

YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7

  • Cancer Res. 2021 May 15;81(10):2651-2665. doi: 10.1158/0008-5472.CAN-20-0066.
Jingnan Pi # 1 2,  Wen Wang # 1 2,  Ming Ji 3,  Xiaoshuang Wang 1 2,  Xueju Wei 1 2,  Jing Jin 3,  Tao Liu 4,  Jiaqi Qiang 1 2,  Zhihong Qi 5,  Feng Li 6,  Yue Liu 1 2,  Yanni Ma 1 2,  Yanmin Si 1 2,  Yue Huo 1 2,  Yufeng Gao 1 2,  Yiying Chen 1 2,  Lei Dong 7,  Rui Su 7,  Jianjun Chen 7,  Shuan Rao 8,  Ping Yi 4,  Shuyang Yu 5,  Fang Wang 9 2,  Jia Yu 9 2 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • 2 The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, China.
  • 3 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Department of Obstetrics and Gynecology, Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 State Key Laboratory of AgroBiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  • 6 Department of Molecular Biology, Shanxi Cancer Hospital, Affiliated Cancer Hospital of Shanxi Medical University, Shanxi, China.
  • 7 Department of Systems Biology and Gehr Family Center for Leukemia Research, The Beckman Research Institute of City of Hope, Monrovia, California.
  • 8 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 9 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China. [email protected] [email protected].
  • 10 Medical Epigenetic Research Center, Chinese Academy of Medical Sciences, Beijing, China.
  • # Contributed equally.
PMID: 32788173 DOI: 10.1158/0008-5472.CAN-20-0066
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.

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