Role and mechanisms of m6A demethylases in digestive system tumors

Abstract

Digestive system tumors are common malignancies in humans, often accompanied by high mortality and poor prognosis. Therefore, intensive research on the pathogenesis of digestive system tumors is imperative. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotes and exerts regulatory effects on RNA expression and metabolism, including splicing, translation, stability, decay, and transport. m6A demethylases belong to the AlkB family of dioxygenases that can catalyze m6A demethylation. Accumulating evidence in recent years has shown that abnormal m6A levels caused by m6A demethylases play crucial roles in different aspects of human cancer development. In this review, we comprehensively summarize the recent findings on the functions and underlying molecular mechanisms of m6A demethylases in cell proliferation, apoptosis, migration, invasion, metastasis, angiogenesis, resistance to chemo- and radiotherapy, and the tumor immune microenvironment (TIME) of digestive system tumors. Furthermore, we discuss the therapeutic potential of targeting these m6A demethylases for treatment.

Keywords: AlkB homolog 5 (ALKBH5); cancer therapeutics; digestive system tumors; fat mass and obesity associated protein (FTO); m6A.

Figure 1

Mechanism of m6A modification mediated by writers, erasers and readers. Writers including methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), methyltransferase-like 16 (METTL16), wilms tumor 1-associated protein (WTAP), vir like m6A methyltransferase associated (VIRMA/KIAA1429), RNA binding motif protein 15 (RBM15), RNA binding motif protein 15B (RBM15B), zinc finger CCCH-type containing 13 (ZC3H13), zinc finger CCHC-type containing 4 (ZCCHC4), and cap-specific adenosine methyltransferase (CAPAM) are responsible for m6A methylation to target RNAs. Erasers, such as FTO, ALKBH5, and AlkB homolog 3 (ALKBH3) are responsible for removing the m6A modification. Various readers such as YTH domain containing 1 (YTHDC1), YTH domain containing 2 (YTHDC2), YTH domain family 1 (YTHDF1), YTH domain family 2 (YTHDF2), YTH domain family 3 (YTHDF3), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), heterogeneous nuclear ribonucleoprotein C (HNRNPC), heterogeneous nuclear ribonucleoprotein G (HNRNPG), heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), and eukaryotic translation initiation factor 3 (eIF3) recognize m6A and modulate mRNA export, splicing, stability, decay, translation, structure switching, and microRNA (miRNA) processing (Figure was created with figdraw.com).

Figure 2

The functions of m6A demethylases in digestive system tumors. m6A demethylases are involved in various processes in the development of digestive system tumors, including cell proliferation, apoptosis, migration, invasion, metastasis, angiogenesis, resistance to chemo- and radiotherapy, and the TIME.

Figure 3

m6A demethylases promote or inhibit the progression of digestive system tumors by coordinating with reader proteins to target related molecules. A. m6A demethylases regulate the molecular mechanism of CRC. B. m6A demethylases regulate the molecular mechanism of HCC, ICC, HBV-HCC, and NAFLD. C. m6A demethylases regulate the molecular mechanism of GC. D. m6A demethylases regulate the molecular mechanism of PC, PDAC, and pNENs. E. m6A demethylases regulate the molecular mechanism of EC and ESCC.