2. Academic Validation
  3. WNT/β-catenin-suppressed FTO expression increases m6A of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis

WNT/β-catenin-suppressed FTO expression increases m6A of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis

  • Cell Death Dis. 2021 May 8;12(5):462. doi: 10.1038/s41419-021-03739-z.
Xueying Yang 1,  Fei Shao 2,  Dong Guo 3,  Wei Wang 1,  Juhong Wang 1,  Rongxuan Zhu 1,  Yibo Gao 4 5,  Jie He 6 7,  Zhimin Lu 8 9
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
  • 2 The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, 266071, Qingdao, Shandong, China.
  • 3 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.
  • 4 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. gaoyibo@cicams.ac.cn.
  • 5 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. gaoyibo@cicams.ac.cn.
  • 6 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. hejie@cicams.ac.cn.
  • 7 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. hejie@cicams.ac.cn.
  • 8 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China. zhiminlu@zju.edu.cn.
  • 9 Zhejiang University Cancer Center, 310029, Hangzhou, China. zhiminlu@zju.edu.cn.
PMID: 33966037 DOI: 10.1038/s41419-021-03739-z
Abstract

FTO removes the N6-methyladenosine (m6A) modification from genes and plays a critical role in Cancer development. However, the mechanisms underlying the regulation of FTO and its subsequent impact on the regulation of the epitranscriptome remain to be further elucidated. Here, we demonstrate that FTO expression is downregulated and inversely correlated with poor survival of lung adenocarcinoma patients. Mechanistically, Wnt signaling induces the binding of EZH2 to β-catenin. This protein complex binds to the LEF/TCF-binding elements at the promoter region of FTO, where EZH2 enhances H3K27me3 and inhibits FTO expression. Downregulated FTO expression substantially enhances the m6A levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced m6A levels on MYC mRNA recruit YTHDF1 binding, which promotes MYC mRNA translation and a subsequent increase in glycolysis and proliferation of tumor cells and tumorigenesis. Our findings uncovered a critical mechanism of epitranscriptome regulation by Wnt/β-catenin-mediated FTO downregulation and underscored the role of m6A modifications of MYC mRNA in regulating tumor cell glycolysis and growth.

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