Abstract
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. m6A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m6A modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-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/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC.
Highlights
The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers
We demonstrate that methyltransferase-like 3 (METTL3) is upregulated in ESCC and enhances m6A of APC mRNA, thereby leading to recruitment of YTHDF for APC mRNA degradation and subsequent enhanced aerobic glycolysis, ESCC cell proliferation, tumour formation in mice and poor prognosis in patients
To explore the expression profile of METTL3 in ESCC, which constitutes ~90% of oesophageal cancer[28], we analysed the Cancer Genome Atlas (TCGA) data and found that METTL3 expression was significantly upregulated in 95 ESCC specimens compared to that in 11 adjacent normal oesophageal epithelium tissues (Fig. 1a and Supplementary Fig. 1a)
Summary
The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. M6A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m6A modification of APC, which recruits YTHDF for APC mRNA degradation. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC. RNA modifications reveal a new level of posttranscriptional gene expression regulation[11,12,13,14,15]. RNA m6A modification and its key m6A methyltransferase METTL3, which forms a heterodimer with METTL14, have been reported to be essential for tumour progression in several types of cancer[23,24,25]. We demonstrate that METTL3 is upregulated in ESCC and enhances m6A of APC mRNA, thereby leading to recruitment of YTHDF for APC mRNA degradation and subsequent enhanced aerobic glycolysis, ESCC cell proliferation, tumour formation in mice and poor prognosis in patients
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