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.
The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, 266071, Qingdao, Shandong, China.
Cell Death Dis. 2021 May 8;12(5):462. doi: 10.1038/s41419-021-03739-z.
FTO removes the N6-methyladenosine (mA) 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 mA levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced mA 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 mA modifications of MYC mRNA in regulating tumor cell glycolysis and growth.
FTO 去除基因中的 N6-甲基腺苷（mA）修饰，在癌症发展中发挥关键作用。然而，FTO 的调控机制及其对表观转录组调控的后续影响仍有待进一步阐明。在这里，我们证明 FTO 的表达下调与肺腺癌患者不良预后呈负相关。在机制上，Wnt 信号诱导 EZH2 与 β-catenin 结合。该蛋白复合物与 FTO 启动子区域的 LEF/TCF 结合元件结合，EZH2 增强 H3K27me3 并抑制 FTO 的表达。下调的 FTO 表达显著增加了大量关键途径（特别是代谢途径基因）中基因 mRNA 的 mA 水平，如 MYC。增强的 MYC mRNA 的 mA 水平募集 YTHDF1 结合，促进 MYC mRNA 的翻译，并随后增加肿瘤细胞的糖酵解和增殖以及肿瘤发生。我们的研究结果揭示了 Wnt/β-catenin 介导的 FTO 下调对表观转录组调控的关键机制，并强调了 MYC mRNA 的 mA 修饰在调节肿瘤细胞糖酵解和生长中的作用。
