Effects of writers, erasers and readers within miRNA-related m6A modification in cancers

Abstract

Background: As one of the most abundant post-transcriptional mRNA modifications, N6-methyladenosine (m6A) has attracted extensive attention from scientists. Emerging evidence indicates that m6A modification plays a significant role in cancer-related signalling pathways. Existing research demonstrates that m6A modifications were also identified in miRNAs and contribute to cancer-related signalling pathways.

Methods: A literature retrieval has been performed to collect m6A-miRNA-related original articles published in recent years. Later, a systematic analysis has been conducted to abstract and classify the relationships between m6A modification and miRNAs, and their contributions to tumorigenesis and cancer development.

Results: Accumulating literature provides important insights into multiple relationships between m6A modifications and miRNAs. Mechanically, m6A writer and eraser alter pri-miRNAs m6A levels, and m6A readers could dually modulate pri-miRNAs processing and pri-miRNAs degradation. It is also been demonstrated that miRNAs impair m6A regulators' translation to influence m6A medication function in return. Aberrant expressions of m6A regulators and miRNAs could dysregulate proliferative, apoptosis, cell adhesion-related, and malignant transformation signalling pathways, and contribute to tumour occurrence and development.

Conclusion: This review summarizes the interrelationship between m6A modification and miRNAs; highlights the combined effects of each type of m6A regulator and miRNAs in cancers. These findings enhance our understanding of m6A-miRNAs' multiple interactions and significant modulatory role in tumorigenesis and progression.

FIGURE 1

The dynamic process of m6A modification and diverse functions of m6A readers. (A) Methyl was installed at N6 of adenosine by m6A methyltransferase complex which consists of METTL3, METTL14, WTAP, RBM15, VIRMA and ZC3H13. In addition, METTL16 and NSun2 could function individually. M6A modification could be removed by demethyltransferases FTO and ALKBH5. m6A writers and erasers dynamically regulate RNA m6A levels, followed by recognition of m6A binding proteins. Different readers manipulate diverse RNA metabolism processes. (B) In the nucleus, readers could mediate mRNA alternative splicing, maintain mRNA stability and primary miRNAs processing. (C) In the cytoplasm, readers could promote mRNAs translation and the exact opposite function, mRNAs degradation

FIGURE 2

The patterns of interaction between m6A modification and miRNAs. (A) m6A modification mediates pri‐miRNAs processing. m6A writer deposits methyl at the m6A motif of pri‐miRNA followed by m6A reader recognizing it. Part of readers like HNRNP2B1, NKAP and YTHDC1 recruit microprocessor complex for flanking slicing, subsequently receiving a precursor miRNA, while YTHDF2 could accelerate pre‐miRNA degradation. (B) miRNAs target 3′s UTR of m6A regulators. miRNAs could induce m6A level alteration or impede m6A reader function implementation through targeting m6A regulators' 3′ UTR. (C) miRNAs orchestrate with m6A regulators to exert their intrinsic functions. miRNAs could assist m6A methylation and demethylation by interacting with the writer and eraser respectively. miRNA targets mRNA 3′UTR in an m6A‐dependent way

FIGURE 3

M6A modification and miRNAs are involved in various cancers. Articles concerning m6A and miRNAs cover the digestive system, respiratory system, urogenital system, neural system, skeletal system and endocrine system