m⁶A RNA modification modulates PI3K/Akt/mTOR signal pathway in Gastrointestinal Cancer

Abstract

Rationale: Methylation at the N6 position of adenosine (m 6 A) 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 m 6 A are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of m 6 A in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known m 6 A 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 m 6 A regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. m 6 A modification sites were predicted by SRAMP. m 6 A related SNPs were analyzed by m 6 ASNP. The modulation of m 6 A on its related pathway members was validated by m 6 A-seq, real-time PCR and phosphor-MAPK array. Results: We found that m 6 A 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 m 6 A modification in most human cancers, including GI cancer, which was further verified by m 6 A-Seq and phospho-MAPK array. Conclusions: Our findings suggest that m 6 A RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer.

Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma

“…Other m 6 A readers, including YTHDF1, YTHDF2, YTHDF3, and YTHDC1, also determine RNA stability 12 , 13 . Intriguingly, we observed a distinct oncogenic influence of several m 6 A RNA enzymes in different tumors 14 . In particular, METTL14, targeting MYB and MYC, was proven to be required for the growth of acute myeloid leukemia cells, driving the self-renewal process of leukemia stem/initiation cells 15 .…”

Emerging role of RNA modification N6-methyladenosine in immune evasion

“…METTL14 deficiency in mice could inhibit the naive T cells into induced T reg cells 42 . Disruption of mTOR signal in Treg cells leads to Treg suppressive activity in immune tolerance because foreign signals through the TCR and IL-2 provide major inputs for mTOR activation 54 , while another study reports that the m6A modification could upregulated PI3K/Akt/mTOR signal pathway in cancer 55 . It indirectly indicates that m6A machinery enables efficient mTOR signaling to promote Treg suppressive function.…”

Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma

“…Therefore, the search for specific molecular markers of HNSCC is of great significance for better understanding of its progress and for developing new therapeutic methods. At present, an increasing number of studies have concentrated on the mechanism of pathogenesis, especially genetic and epigenetic events, at the molecular level ( 27 ). Currently, m 6 A modification has been reported to play a vital function in cell infiltration in the tumor microenvironment, and the m 6 A modification pattern can be used to help identify different immune phenotypes in gastric cancer ( 28 ).…”