Rationale: Methylation at the N6 position of adenosine (m⁶A) is the most prevalent RNA modification within protein-coding mRNAs in mammals, and it is a reversible modification with various important biological functions. The formation and function of m⁶A are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of m⁶A in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known m⁶A writer, eraser, and reader proteins in GI cancer. Methods: Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used. Gene alteration and pathway analysis were done in cBioportal. The protein network of m⁶A regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. m⁶A modification sites were predicted by SRAMP. m⁶A related SNPs were analyzed by m⁶ASNP. The modulation of m⁶A on its related pathway members was validated by m⁶A-seq, real-time PCR and phosphor-MAPK array. Results: We found that m⁶A regulators were mostly upregulated in GI cancer and their differential expression significantly influenced the overall survival of patients with GI cancer. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways were found to be potentially affected by m⁶A modification in most human cancers, including GI cancer, which was further verified by m⁶A-Seq and phospho-MAPK array. Conclusions: Our findings suggest that m⁶A RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer.

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