N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

Abstract

The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex, removed by a demethylase, and recognized by reader proteins. Mechanistically, m6A modification regulates the expression levels of mRNA and nocoding RNA by modulating the fate of modified RNA molecules, such as RNA splicing, nuclear transport, translation, and stability. Several studies have shown that m6A modification is dysregulated in the progression of multiple diseases, especially human tumors. We emphasized that the dysregulation of m6A modification affects different signal transduction pathways and involves in the biological processes underlying tumor cell proliferation, apoptosis, invasion and migration, and metabolic reprogramming, and discuss the effects on different cancer treatment.

Keywords: Cancer progression; N6-methyladenosine; RNA fate; Signal transduction pathway; Therapy.

Fig. 1

Function and mechanisms of N6-methyladenosine (m6A) regulators. The m6A modification is deposited by methyltransferase complex including METTL3, METTL14, WTAP, VIRMA, RBM15, and ZC3H13, or by METTL16 alone. The m6A modification is removed by demethylase FTO or ALKBH5. Readers could recognize and affect the fate of m6A modified RNA molecules, including RNA splicing, export, translation, decay, and so on

Fig. 2

N6-methyladenosine can influence cancer cell proliferation. a m6A modification regulates the cell cycle and subsequent cell proliferation. At the G1/S checkpoint, m6A modification can regulate CDK4, CCND1, CCNE1, CDK2, and E2F1 post-transcriptionally, and affect the G1/S transition. While at the G2/M checkpoint, m6A modification can affect cell cycle progression by degrading ETS1 and PER1. b m6A modification can affect cell proliferation through affecting the fate of key molecules associated with distinct signaling pathways, such as nuclear factor-kB (NF-kB), Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and AKT

Fig. 3

N6-methyladenosine and cell apoptosis associated signaling pathway. N6-methyladenosine can get involved in three key apoptosis associated signaling pathways as follows-. a In the mitochondrial pathway, m6A modification can affect cell apoptosis by regulating the fate of Bcl-2 and BMF. b In endoplasmic reticulum pathway, m6A modification can affect cell apoptosis by regulating SEC62. c In death receptor pathway, m6A modification can influences cell apoptosis by regulating TNFRSF2

Fig. 4

N6-methyladenosine and cancer invasion and migration. a m6A modification can regulate the tumor cell invasion and metastasis by affecting the different signaling pathways, including mitogen-activated protein kinase (MAPK), AKT, and Hippo signaling pathways. b m6A modification can affect the process of epithelial-mesenchymal transition (EMT) by regulating the tumor growth factor beta (TGF-β) and Hippo signaling pathway, or by regulating the roles of key molecules associated with EMT, such as E-cadherin, Snail, and Zeb1

Fig. 5

N6-methyladenosine and cancer metabolic reprogramming. a m6A modification can participate in the glycolysis process by affecting the RNA fate of key enzymes involved in the glycolysis process. b The m6A modification can also inhibit the aerobic respiration of cells, allowing more glucose to participate in glycolysis