METTL3 as a master regulator of translation in cancer: mechanisms and implications

Abstract

Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m⁶A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m⁶A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m⁶A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m⁶A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.

Graphical Abstract

Figure 1.

Translation process in eukaryotes. Translation involves four main phases: initiation (steps 1 to 5), elongation (steps 6 to 9), termination (step 10), and recycling (step 11). Eukaryotic translation begins with the assembly of the 43S pre-initiation complex, comprising the 40S ribosomal subunit, eIF2-GTP-Met-tRNAiMET, eIF3, eIF5, eIF1 and eIF1A. The target transcript is activated by the eIF4F complex (eIF4E, eIF4G, eIF4A), eIF4B and PABP, which promotes the loop conformation. This mRNA then binds to the 43S pre-initiation complex, forming the 48S complex, initiating the start codon recognition scan. Upon recognition, the 60S ribosomal subunit and eIF5B-GTP associate, releasing cap-binding factors, eIF2-GDP, eIF1 and eIF5. Elongation involves cycles in which mRNA moves through the ribosome, with tRNAs in the P site carrying the polypeptide, and eEF1α-GTP incorporating new aminoacyl tRNA into the A site. Peptide transfer occurs, followed by ribosome translocation along the mRNA. This cycle repeats until a stop codon is recognized by eRF1 and eRF3, releasing the peptide. This is followed by Rli1/ABCE1 binding, hydrolysis and dissociation of ribosomal subunits. Finally, tRNA, mRNA, and terminator factors are released, resulting in separated ribosomal subunits for new translation cycles.

Figure 2.

Schematic representation of m⁶A writers, erasers and readers and their impact on mRNA metabolism. m⁶A is deposited by the m⁶A methyltransferase complex, consisting of the heterodimer METTL3-METTL14 and other accessory proteins (WTAP, VIRMA, HAKAI, ZC3H13, RBM15/15B). m⁶A is erased by the demethylases FTO or ALKBH5. In the nucleus, m⁶A regulates mRNA export, splicing and degradation of chromosome-associated RNAs (caRNA). In the cytoplasm m⁶A influences mRNA stability, both cap-dependent and independent translation, and decay. Asterisk (*) indicates that more than one reader protein can mediate a specific mRNA fate.

Figure 3.

Publication trends on m⁶A and cancer from PubMed. The figure depicts the yearly publication count from a combined Pubmed search using the terms ‘N6-methyladenosine’ or ‘N(6)-methyladenosine’ and ‘cancer’. It highlights significant milestones, including the initial discovery of m⁶A in 1974 the pioneering studies on METTL3 (named MTA or MTA70) in Arabidopsis thaliana in 2008, and the development of the first high throughput techniques -MeRIP-seq and m⁶A-seq-enabling m⁶A mapping in 2012.

Figure 4.

Mechanisms of translational regulation mediated by m⁶A sites in 5′UTR, coding sequences (CDS) and 3′UTR regions. In the 5′UTR, under certain stress conditions, eIF3 can act as a reader and recruit the 43S initiation complex, YTHDF2 protects m⁶A-transcripts from FTO demethylation and ABCF1 can recruit eIF3 and initiate translation. In the CDS, IGF2BP3 can bind to the m⁶A mark and mediate the switch of transcripts from polysomes to P-bodies, whereas YTHDC2 contributes to the resolution of RNA secondary structures and alleviates ribosome stalling. Finally, in the 3′UTR region, m⁶A is mainly recognized by either YTHDF1 or YTHDF3 to mediate the cap-dependent translation by promoting the loop conformation of the RNA.

Figure 5.

Translation regulation mediated by cytoplasmic METTL3. Schematic representation of the mechanisms by which METTL3 in the cytoplasm enhances the translation of specific mRNAs in cancer cells. In lung cancer, METTL3 has been described to act as an m⁶A reader in the 3′UTR of oncogenic transcripts, enhancing their translation through direct interaction with eIF3h. In gastric cancer, independent of m⁶A, METTL3 binds PABPC1 to facilitate its interaction with the cap-binding complex and promote the loop configuration, ultimately promoting gastric tumorigenesis. Cytoplasmic METTL3 has been suggested to promote the translation of PES1, independent of m⁶A, in chronic myeloid leukemia, but possible interacting partners and specific mechanisms have not been determined. Acetylation of METTL3 mediates its cytoplasmic localization in breast cancer.