N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

Abstract

N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.

Keywords: Cancer; Drug discovery; Therapy resistance; m6A; m6A methyltransferase.

Fig. 1

Schematic illustration of the reported m6A methyltransferase complex (MTC) of human RNAs. a Most of the mRNAs are methylated by the METTL3-METTL14 complex. This complex is composed of other adaptor proteins, including WTAP, VIRMA, RBM15/15B, ZC3H13 and HAKAI. These adaptors may help in determining the specific sites of m6A methylation. For example, VIRMA mediates preferential m6A mRNA methylation in the 3'UTR, while HAKAI affects m6A modification distributed in the 5’UTR. b m6A in 28S and 18S rRNA is the result of ZCCHC4 and METTL5-TRMT112 complex activity, respectively. c METTL16 mediates m6A modification in U6 snRNA and a small proportion of other mRNAs through specific structural recognition

Fig. 2

m6A methyltransferase regulation of the core pathways in cancer. The key cancer pathways, including the MYC pathway (a), Wnt/β-Catenin pathway (b), PI3K/AKT/mTOR pathway (c), p53 (d), BCL-2 (e), and other key genes (f), are regulated by the m6A methyltransferases METTL3/METTL14/WTAP. The schematic illustration shows the core genes in the related pathway that target different m6A methyltransferases, as well as the modulated upstream and downstream genes in these pathways

Fig. 3

Overview of multiple functions of m6A methyltransferases in therapy resistance. As the key regulator of m6A, m6A methyltransferases have been found to regulate resistance to various therapy including chemotherapy (a), targeted therapy (b), immunotherapy (c) and radiotherapy (d)

Fig. 4

Potential approaches for targeting m6A methyltransferases. a Targeting strategy with small-molecule modulators. Schematic domain structure of the METTL3-METTL14 complex with SAM binding (left). STM2457, a catalytic inhibitor of METTL3 that competes with SAM for the SAM-binding pocket, represents the general strategy of m6A methyltransferase modulator development (right). b Targeting strategy related to limit SAM level. Restriction of SAM levels by 3-deazaadenosine (3-DA) reduces m6A levels by blocking SAHH and subsequently elevating SAH levels. Specifically, limiting the level of dietary methionine, which is required for SAM synthesis, can also regulate METTL3 activity. c Targeting strategy for the use of specific miRNAs to inhibit METTL3/METTL14 expression. d Targeting strategy of CRISPR-based site-specific m6A modification