Function of N6-Methyladenosine Modification in Tumors.

Yu Peng,Yuxin Zuo,Nan Zhang,Lielian Zuo,Alessandro Granito

doi:10.1155/2021/6461552

Abstract

N6-Methyladenosine (m6A) modification is a dynamic and reversible methylation modification at the N6-position of adenosine. As one of the most prevalent posttranscriptional methylation modifications of RNA, m6A modification participates in several mRNA processes, including nuclear export, splicing, translation, and degradation. Some proteins, such as METTL3, METTL14, WTAP, ALKBH5, FTO, and YTHDF1/2/3, are involved in methylation. These proteins are subdivided into writers (METTL3, METTL14, WTAP), erasers (ALKBH5, FTO), and readers (YTHDF1/2/3) according to their functions in m6A modification. Several studies have shown that abnormal m6A modification occurs in tumors, including colorectal cancer, liver cancer, breast cancer, nasopharyngeal carcinoma, and gastric cancer. The proteins for m6A modification are involved in tumor proliferation, angiogenesis, metastasis, immunity, and other processes. Herein, the roles of m6A modification in cancer are discussed, which will improve the understanding of tumorigenesis, as well as the diagnosis, treatment, and prognosis of tumors.

Highlights

Epigenetics is the study of gene expression regulated by modifications that do not alter the gene sequence
Readers recognize the adenosine bases that are modified by N6 methylation, thereby activating downstream regulatory pathways. is process involves multiple proteins. e m6A writer comprises a methyltransferase complex, which includes the core components of methyltransferase-like 3 (METTL3) and methyltransferase like 14 (METTL14), as well as WT1-associated protein (WTAP), KIAA1429, and other regulatory subunits [5, 6]. e main role of the writer is to catalyze the m6A modification of adenylate on mRNA. e erasers are demethylases, which reverse m6A modification and include α-ketoglutarate-dependent dioxygenase ALKB homolog 5 (ALKBH5) and fatmass and obesity-associated protein (FTO) [7]
Transcript levels of IFN-α, IFN-β, and IFN-c were observed to be downregulated after knockdown of METTL14/ YTHDF1 in gastric cancer cell lines, while IFN-α and IFN-β were involved in promoting the accumulation of pDCs in tumor microenvironment (TME) and the expression of PD-L1 in CD4+CD25+Tregs [68,69,70]

Summary

Introduction

Epigenetics is the study of gene expression regulated by modifications that do not alter the gene sequence. METTL3 was significantly elevated and promoted the proliferation of tumor cells by suppressing the expression of the suppressor of the cytokine signaling 2 gene in colorectal and liver cancers [15]. By recognizing m6A modification in cyclin D1 mRNA, IGF2BP3 inhibited DNA replication in the S phase and the proliferation of colorectal cancer cells (Figure 1(a)) [17]. MiR-96 directly targets AMPKα2, leading to increased expression of FTO and subsequent activation of MYC to promote the proliferation of CRC cells (Figure 1(a)) [21]. Lnc942 directly binds to METTL14 by harboring a specific METTL14 binding domain (+176-+265), thereby stabilizing the expression and translation of downstream targets, such as CXCR4 and CYP1B1, and promoting the proliferation of tumor cells [30] (Figure 1(a))

M6A Modification and Angiogenesis

M6A Modifications and Differentiation

M6A Modification and Metastasis

M6A Modifications and Apoptosis

M6A Modifications and Clinical Applications

Findings

10. Conclusions