期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23501-5
关键词
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资金
- Ministry of Science and Technology of the People's Republic of China (the National Key R&D Program of China) [2018YFC1312100, 2018YFC1313100, 2020YFA0803300]
- National Natural Science Foundation of China [81972316, 82002445, 82030074]
- Beijing Nova Program [Z181100006218032]
- CAMS Innovation Fund for Medical Sciences [CIFMS: 2017-I2M-1-005, 2017-I2M-2-003]
- Natural Science Foundation of Zhejiang Province [LD21H160003]
- Zhejiang University Research Fund [188020*194221901/029]
- Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang [2019R01001]
This study demonstrates that METTL3 downregulates APC by upregulating its m(6)A modification and recruiting YTHDF2 for APC mRNA degradation, leading to enhanced glycolysis and tumor growth in esophageal cancer.
The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. m(6)A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m(6)A modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of beta -catenin and beta -catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/beta -catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC. The epitranscriptomic regulation of adenomatous polyposis coli (APC) tumour suppressor gene in cancers is unclear. Here the authors show that N6-methyladenosine methylation writer METTL3 downregulates APC by recruiting YTHDF2 for APC mRNA degradation, and that this promotes glycolysis and tumour growth in oesophageal cancers.
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