Overview of the interplay between m6A methylation modification and non-coding RNA and their impact on tumor cells

Abstract

N6-methyladenosine (m6A) is one of the most common internal modifications in eukaryotic RNA. The presence of m6A on transcripts can affect a series of fundamental cellular processes, including mRNA splicing, nuclear transportation, stability, and translation. The m6A modification is introduced by m6A methyltransferases (writers), removed by demethylases (erasers), and recognized by m6A-binding proteins (readers). Current research has demonstrated that m6A methylation is involved in the regulation of malignant phenotypes in tumors by controlling the expression of cancer-related genes. Non-coding RNAs (ncRNAs) are a diverse group of RNA molecules that do not encode proteins and are widely present in the human genome. This group includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI interaction RNAs (piRNAs). They function as oncogenes or tumor suppressors through various mechanisms, regulating the initiation and progression of cancer. Previous studies on m6A primarily focused on coding RNAs, but recent discoveries have revealed the significant regulatory role of m6A in ncRNAs. Simultaneously, ncRNAs also exert their influence by modulating the stability, splicing, translation, and other biological processes of m6A-related enzymes. The interplay between m6A and ncRNAs collectively contributes to the occurrence and progression of malignant tumors in humans. This review provides an overview of the interactions between m6A regulatory factors and ncRNAs and their impact on tumors.

Keywords: N6-methyladenosine methylation (m6A methylation); m6A regulatory factors; non-coding RNA (ncRNA); tumor.

Figure 1

Functions of m6A modifications. M6A modifications are catalyzed by the methyltransferase complex consisting of METTL3, METTL14 and their cofactors WTAP, ZC3H13 (writers). The removal of m6A modifications relies on the demethylases FTO and ALKBH5 (erasers). M6A modifications are facilitated by the m6A binding proteins YTHDF1-3, YTHDC1-2, IGF2BP1-3, and HNRNPA2B1 (readers). In the nucleus, YTHDC1 is associated with alternative splicing and nuclear export; HNRNPC is associated with pre-mRNA processing and structure switching, and HNRNPA2B1 is associated with primary miRNA processing, alternative splicing and structure switching. In the cytoplasm, YTHDF1/2/3 are associated with RNA translation, and IGF2BP1/2/3 are associated with stability. m6A, N6-methyladenosine.

Figure 2

M6A regulatory factors regulate tumor proliferation, migration, invasion, apoptosis, and drug resistance through ncRNAs. m6A, N6-methyladenosine; ncRNA, non-coding RNA; lncRNA, long non-coding RNA; circRNA, circular RNA; miRNA, microRNA; pri-miRNA, primary microRNA.

Figure 3

Non-coding RNAs regulate tumor phenotypes such as proliferation, migration, apoptosis, and drug resistance through m6A regulatory factors. m6A, N6-methyladenosine; lnc RNA, long non-coding RNA; circRNA, circular RNA; miRNA, microRNA; piRNA, PIWI-interacting RNA.

Figure 4

M6A-related non-coding RNAs serve as prognostic markers for tumors in different cancer types (124-147). m6A, N6-methyladenosine, lncRNA, long non-coding RNA.

Figure 5

The role of m6A-related non-coding RNAs as targets in cancer therapy. (A) Tazemetostat can reduce the expression of LOC606724 (an m6A-associated lncRNA) in exosomes, and in combination with bortezomib, synergistically inhibits tumor growth in a mouse model of multiple myeloma. (B) A polyethylene glycolyzed poly (lactic acid/glycolic acid) nanoplatform (PLGA-PEG NP) loaded with LINC00958 siRNA (si-LINC00958) PLGA-PEG (si-LINC00958) NPs suppress tumor growth in a mouse model of liver cancer. (C) LncRNA ABL is an m6A-related lncRNA. Polyethylene glycol-modified cationic liposomes (PEG-CLs) loaded with ABL-specific siRNA PEG-CLs, when combined with paclitaxel, can synergistically inhibit the development of gastric cancer. (D) M6A-modified circQSOX1 can promote immune evasion of colorectal cancer in a specific way. Combination therapy with sh-circQSOX1 and anti-CTLA-4 can inhibit the development of CRC by overcoming resistance to immunotherapy. m6A, N6-methyladenosine.