Multiple Functions and Mechanisms Underlying the Role of METTL3 in Human Cancers

Overview

Journal Front Oncol

Specialty Oncology

Date 2020 Jan 11

PMID 31921660

Citations 49

Authors

Wenhui Zheng

Xiaoshen Dong

Yan Zhao

Shuo Wang

Haiyang Jiang

Mingdi Zhang

Xinyu Zheng

Ming Gu

Affiliations

Soon will be listed here.

Abstract

Methyltransferase-like 3 (METTL3), a predominantly catalytic enzyme in the N-methyladenosine (mA) methyltransferase system, is dysregulated and plays a dual role (oncogene or tumor suppressor) in different human cancers. The expression and pro- or anticancer role of METTL3 in different cancers remain controversial. METTL3 is implicated in many aspects of tumor progression, including tumorigenesis, proliferation, invasion, migration, cell cycle, differentiation, and viability. Most underlying mechanisms involve multiple signaling pathways that rely on mA-dependent modification. However, METTL3 can also modulate the cancer process by directly promoting the translation of oncogenes via interaction with the translation initiation machinery through recruitment of eukaryotic translation initiation factor 3 subunit h (eIF3h). In this review, we summarized the current evidence on METTL3 in diverse human malignancies and its potential as a prognostic/ therapeutic target.

Citing Articles

Multimodal tumor suppression by METTL3 gene knockdown in melanoma and colon cancer cells.

Bazargani A, Taha M, Mohammad Soltani B, Javeri A Histochem Cell Biol. 2024; 163(1):21.

PMID: 39720980 DOI: 10.1007/s00418-024-02346-1.

Role of m6A Methylation Regulators in the Diagnosis and Subtype Classification of COPD Based on the GEO Database.

Zhang P, Gao N, Li X, Zheng X, Kong D, Wu J J Cell Mol Med. 2024; 28(22):e70226.

PMID: 39580709 PMC: 11585962. DOI: 10.1111/jcmm.70226.

Decoding the epitranscriptome: a new frontier for cancer therapy and drug resistance.

Tang L, Tian H, Min Q, You H, Yin M, Yang L Cell Commun Signal. 2024; 22(1):513.

PMID: 39434167 PMC: 11492518. DOI: 10.1186/s12964-024-01854-w.

The METTL3/TRAP1 axis as a key regulator of 5-fluorouracil chemosensitivity in colorectal cancer.

Kang Q, Hu X, Chen Z, Liang X, Xiang S, Wang Z Mol Cell Biochem. 2024; 480(3):1865-1889.

PMID: 39287889 PMC: 11842504. DOI: 10.1007/s11010-024-05116-8.

Functions and mechanisms of RNA mA regulators in breast cancer (Review).

Yang Y, Gao F, Ren L, Ren N, Pan J, Xu Q Int J Oncol. 2024; 65(3).

PMID: 39054967 PMC: 11299767. DOI: 10.3892/ijo.2024.5674.

References

Dahal U, Le K, Gupta M . RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2. Melanoma Res. 2019; 29(4):382-389. DOI: 10.1097/CMR.0000000000000580. View

Hua W, Zhao Y, Jin X, Yu D, He J, Xie D . METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol Oncol. 2018; 151(2):356-365. DOI: 10.1016/j.ygyno.2018.09.015. View

He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P . ALKBH5 Inhibits Pancreatic Cancer Motility by Decreasing Long Non-Coding RNA KCNK15-AS1 Methylation. Cell Physiol Biochem. 2018; 48(2):838-846. DOI: 10.1159/000491915. View

Wang X, He J, Yu S, Yu J . [Methyltransferase-like 3 Promotes the Proliferation of Acute Myeloid Leukemia Cells by Regulating N6-methyladenosine Levels of MYC]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018; 40(3):308-314. DOI: 10.3881/j.issn.1000-503X.2018.03.002. View

Zheng G, Dahl J, Niu Y, Fedorcsak P, Huang C, Li C . ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2012; 49(1):18-29. PMC: 3646334. DOI: 10.1016/j.molcel.2012.10.015. View

Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z . METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 2019; 18(1):142. PMC: 6790244. DOI: 10.1186/s12943-019-1065-4. View

Haussmann I, Bodi Z, Sanchez-Moran E, Mongan N, Archer N, Fray R . mA potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature. 2016; 540(7632):301-304. DOI: 10.1038/nature20577. View

Tong J, Flavell R, Li H . RNA mA modification and its function in diseases. Front Med. 2018; 12(4):481-489. DOI: 10.1007/s11684-018-0654-8. View

Lin S, Liu J, Jiang W, Wang P, Sun C, Wang X . METTL3 Promotes the Proliferation and Mobility of Gastric Cancer Cells. Open Med (Wars). 2019; 14:25-31. PMC: 6419388. DOI: 10.1515/med-2019-0005. View

10.

Zhang C, Zhang M, Ge S, Huang W, Lin X, Gao J . Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K-Akt signaling in gastric cancer. Cancer Med. 2019; 8(10):4766-4781. PMC: 6712480. DOI: 10.1002/cam4.2360. View

11.

Uddin M, Roy K, Hosain S, Khiste S, Hill R, Jois S . An N-methyladenosine at the transited codon 273 of p53 pre-mRNA promotes the expression of R273H mutant protein and drug resistance of cancer cells. Biochem Pharmacol. 2018; 160:134-145. PMC: 6407121. DOI: 10.1016/j.bcp.2018.12.014. View

12.

Visvanathan A, Patil V, Arora A, Hegde A, Arivazhagan A, Santosh V . Essential role of METTL3-mediated mA modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2017; 37(4):522-533. DOI: 10.1038/onc.2017.351. View

13.

Geula S, Moshitch-Moshkovitz S, Dominissini D, AlFatah Mansour A, Kol N, Salmon-Divon M . Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science. 2015; 347(6225):1002-6. DOI: 10.1126/science.1261417. View

14.

Liu J, Eckert M, Harada B, Liu S, Lu Z, Yu K . mA mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018; 20(9):1074-1083. PMC: 6245953. DOI: 10.1038/s41556-018-0174-4. View

15.

Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson S . Promoter-bound METTL3 maintains myeloid leukaemia by mA-dependent translation control. Nature. 2017; 552(7683):126-131. PMC: 6217924. DOI: 10.1038/nature24678. View

16.

Pan Y, Ma P, Liu Y, Li W, Shu Y . Multiple functions of mA RNA methylation in cancer. J Hematol Oncol. 2018; 11(1):48. PMC: 5870302. DOI: 10.1186/s13045-018-0590-8. View

17.

Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M . The mA methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene. 2019; 38(19):3667-3680. DOI: 10.1038/s41388-019-0683-z. View

18.

Zhang J, Bai R, Li M, Ye H, Wu C, Wang C . Excessive miR-25-3p maturation via N-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun. 2019; 10(1):1858. PMC: 6478927. DOI: 10.1038/s41467-019-09712-x. View

19.

Peng S, Xiao W, Ju D, Sun B, Hou N, Liu Q . Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med. 2019; 11(488). DOI: 10.1126/scitranslmed.aau7116. View

20.

Wang X, Zhao B, Roundtree I, Lu Z, Han D, Ma H . N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161(6):1388-99. PMC: 4825696. DOI: 10.1016/j.cell.2015.05.014. View