Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Acute Myeloid Leukemia | Review

The biological function of m6A reader YTHDF2 and its role in human disease

Authors: Jin-yan Wang, Ai-qing Lu

Published in: Cancer Cell International | Issue 1/2021

Login to get access

Abstract

N6-methyladenosine (m6A) modification is a dynamic and reversible post-transcriptional modification and the most prevalent internal RNA modification in eukaryotic cells. YT521-B homology domain family 2 (YTHDF2) is a member of m6A “readers” and its role in human diseases remains unclear. Accumulating evidence suggests that YTHDF2 is greatly implicated in many aspects of human cancers and non-cancers through various mechanisms. YTHDF2 takes a great part in multiple biological processes, such as migration, invasion, metastasis, proliferation, apoptosis, cell cycle, cell viability, cell adhesion, differentiation and inflammation, in both human cancers and non-cancers. Additionally, YTHDF2 influences various aspects of RNA metabolism, including mRNA decay and pre-ribosomal RNA (pre-rRNA) processing. Moreover, emerging researches indicate that YTHDF2 predicts the prognosis of different cancers. Herein, we focus on concluding YTHDF2-associated mechanisms and potential biological functions in kinds of cancers and non-cancers, and its prospects as a prognostic biomarker.
Literature
1.
Boccaletto P. et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res, 2018. 46(D1): D303-d307.
2.
Sánchez-Vásquez E, et al. Emerging role of dynamic RNA modifications during animal development. Mech Dev. 2018;154:24–32.PubMedCrossRef
3.
Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A. 1974;71(10):3971–5.PubMedPubMedCentralCrossRef
4.
Maity, A. and B. Das, N6-methyladenosine modification in mRNA: machinery, function and implications for health and diseases. 2016. 283(9): p. 1607–30.
5.
6.
Dominissini D, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201–6.CrossRefPubMed
7.
Han J, et al. METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 2019;18(1):110.PubMedPubMedCentralCrossRef
8.
9.
Chen S. ALKBH5-mediated m(6)A demethylation of lncRNA PVT1 plays an oncogenic role in osteosarcoma. Stem Cells Int. 2020;20:34.
10.
Wang H, Xu B, Shi J. N6-methyladenosine METTL3 promotes the breast cancer progression via targeting Bcl-2. Gene. 2020;722:144076.PubMedCrossRef
11.
12.
Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019;112:108613.PubMedCrossRef
13.
Jin, D. and J. Guo. m(6)A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC. 2020. 19(1): p. 40.
14.
15.
16.
Müller S, et al. IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner. Nucleic Acids Res. 2019;47(1):375–90.PubMedCrossRef
17.
Huang, H., et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. 2018. 20(3): p. 285–295.
18.
19.
Wu R, et al. Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m(6)A-YTHDF2-dependent manner. Int J Obes (Lond). 2018;42(7):1378–88.CrossRef
20.
Paris J, et al. Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. Genome Biol. 2019;25(1):137-148.e6.
21.
Xie, H., et al. METTL3/YTHDF2 m(6) A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer. 2020. 24(7): p. 4092–4104.
22.
Fei Q. YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. Anal Chem. 2020;18(4):e3000664.
23.
Dai X, et al. YTHDF2 Binds to 5-Methylcytosine in RNA and Modulates the Maturation of Ribosomal RNA. Protein Cell. 2020;92(1):1346–54.
24.
Yu R, et al. m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response. Hepatology, 2019. 20(6).
25.
Wu R, et al. m(6)A methylation controls pluripotency of porcine induced pluripotent stem cells by targeting SOCS3/JAK2/STAT3 pathway in a YTHDF1/YTHDF2-orchestrated manner. Cell Death Dis. 2019;10(3):171.PubMedPubMedCentralCrossRef
26.
Zhu T, et al. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. RNA. 2014;24(12):1493–6.
27.
Ma C, Liao S, Zhu Z. Crystal structure of human YTHDC2 YTH domain. Biochem Biophys Res Commun. 2019;518(4):678–84.PubMedCrossRef
28.
Li F, et al. Structure of the YTH domain of human YTHDF2 in complex with an m(6)A mononucleotide reveals an aromatic cage for m(6)A recognition. Cell Res. 2014;24(12):1490–2.PubMedPubMedCentralCrossRef
29.
Huang G, et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Cell Res. 2016;7:12626.
30.
Wang J, et al. Binding to m(6)A RNA promotes YTHDF2-mediated phase separation. 2020. 11(4): p. 304–307.
31.
Pardo JC, et al., Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going? Int J Mol Sci, 2020. 21(17).
32.
Li R, et al. Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis. J Cell Physiol. 2019;18(1):18.
33.
Chen M, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. 2018. 67(6): p. 2254–2270.
34.
He C, Zhang C. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. PLoS Biol, 2020.
35.
Hou J, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Cell Res. 2019;18(1):163.
36.
Zhong L, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019;442:252–61.PubMedCrossRef
37.
Zhou, S., et al., FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation. 2018. 57(5): p. 590–597.
38.
Li Z, et al. Knockdown of YTH N(6)-methyladenosine RNA binding protein 2 (YTHDF2) inhibits cell proliferation and promotes apoptosis in cervical cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2020;36(3):255–63.PubMed
39.
Liu, T. and S. Yang, Dysregulated N6-methyladenosine methylation writer METTL3 contributes to the proliferation and migration of gastric cancer. 2020. 235(1): p. 548–562.
40.
Zhang J, et al. Knockdown of YTH N(6)-methyladenosine RNA binding protein 2 (YTHDF2) inhibits proliferation and promotes apoptosis in MGC-803 gastric cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017;33(12):1628–34.PubMed
41.
Wang JY, et al. Potential regulatory role of lncRNA-miRNA-mRNA axis in osteosarcoma. Biomed Pharmacother. 2020;121:109627.PubMedCrossRef
42.
Yang J, et al. Circular RNA circ_0001105 Inhibits Progression and Metastasis of Osteosarcoma by Sponging miR-766 and Activating YTHDF2 Expression. Onco Targets Ther. 2020;13:1723–36.PubMedPubMedCentralCrossRef
43.
Xu X, et al. Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway. J Exp Clin Cancer Res. 2019;38(1):497.PubMedPubMedCentralCrossRef
44.
Guo X, et al. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol Cancer. 2020;19(1):91.PubMedPubMedCentralCrossRef
45.
Wu Y, et al. RNA m(6)A Methyltransferase METTL3 Promotes The Growth Of Prostate Cancer By Regulating Hedgehog Pathway. J Hematol Oncol. 2019;12:9143–52.
46.
Li J, et al. Downregulation of N(6)-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N(6)-methyladenosine levels. Oncotarget. 2018;9(3):3752–64.PubMedCrossRef
47.
Li Z, et al. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N(6)-Methyladenosine RNA Demethylase. Cancer Cell. 2017;31(1):127–41.PubMedCrossRef
48.
Nguyen TT, et al. Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia. Genes Chromosomes Cancer. 2006;45(10):918–32.PubMedCrossRef
49.
Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136–52.PubMedCrossRef
50.
51.
Dzierzak E, Bigas A. Blood Development: Hematopoietic Stem Cell Dependence and Independence. Cell Stem Cell. 2018;22(5):639–51.PubMedCrossRef
52.
Walasek MA, van Os R, de Haan G. Hematopoietic stem cell expansion: challenges and opportunities. Ann N Y Acad Sci. 2012;1266:138–50.PubMedCrossRef
53.
Li, Z., et al., Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion. 2018. 28(9): p. 904–917.
54.
Huang S, et al. Author Correction: Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion. Oncogene. 2018;28(10):1042.
55.
Wang, H., et al., Loss of YTHDF2-mediated m(6)A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration. 2018. 28(10): p. 1035–1038.
56.
Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMed
57.
Secher JO, et al. Initial embryology and pluripotent stem cells in the pig–The quest for establishing the pig as a model for cell therapy. Theriogenology. 2016;85(1):162–71.PubMedCrossRef
58.
Heck AM, et al. YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells. ACS Chem Biol. 2020;26(6):739–55.
59.
Li, M., et al., Ythdf2-mediated m(6)A mRNA clearance modulates neural development in mice. 2018. 19(1): p. 69.
60.
Yao Y, et al. METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m(6)A-YTHDF2-dependent manner. Faseb j. 2019;33(6):7529–44.PubMedCrossRef
61.
Merkestein M, et al. FTO influences adipogenesis by regulating mitotic clonal expansion. Nat Commun. 2015;6:6792.PubMedCrossRef
62.
Wu R, et al. FTO regulates adipogenesis by controlling cell cycle progression via m(6)A-YTHDF2 dependent mechanism. Cell Res. 2018;1863(10):1323–30.
63.
Cai M, et al. Loss of m(6) A on FAM134B promotes adipogenesis in porcine adipocytes through m(6) A-YTHDF2-dependent way. IUBMB Life. 2019;71(5):580–6.PubMedCrossRef
64.
65.
Martínez-Pérez, M., et al., Arabidopsis m(6)A demethylase activity modulates viral infection of a plant virus and the m(6)A abundance in its genomic RNAs. 2017. 114(40): p. 10755–10760.
66.
Gonzales-van Horn, S.R. and P. Sarnow, Making the Mark: The Role of Adenosine Modifications in the Life Cycle of RNA Viruses. Cell Host Microbe, 2017. 21(6): p. 661–669.
67.
Hesser, C.R. and J. Karijolich, N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcoma-associated herpesvirus infection. 2018. 14(4): p. e1006995.
68.
Cardelli M, et al. A polymorphism of the YTHDF2 gene (1p35) located in an Alu-rich genomic domain is associated with human longevity. J Gerontol A Biol Sci Med Sci. 2006;61(6):547–56.PubMedCrossRef
69.
Kanatsu-Shinohara M, Shinohara T. Spermatogonial stem cell self-renewal and development. Annu Rev Cell Dev Biol. 2013;29:163–87.PubMedCrossRef
70.
Huang T, et al. YTHDF2 promotes spermagonial adhesion through modulating MMPs decay via m(6)A/mRNA pathway. PLoS Pathog. 2020;11(1):37.
71.
Ivanova I, et al. The RNA m(6)A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence. Mol Cell. 2017;67(6):1059-1067.e4.PubMedPubMedCentralCrossRef
72.
Xie L, Zhao BS, He C. “Gamete On” for m(6)A: YTHDF2 Exerts Essential Functions in Female Fertility. J Cell Mol Med. 2017;67(6):903–5.CrossRef
Metadata
Title
The biological function of m6A reader YTHDF2 and its role in human disease
Authors
Jin-yan Wang
Ai-qing Lu
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-01807-0

Other articles of this Issue 1/2021

Cancer Cell International 1/2021 Go to the issue

Primary research

Ten-gene signature reveals the significance of clinical prognosis and immuno-correlation of osteosarcoma and study on novel skeleton inhibitors regarding MMP9

Primary research

YAP manipulates proliferation via PTEN/AKT/mTOR-mediated autophagy in lung adenocarcinomas

Retraction Note

Retraction Note to: The lncRNA XIST promotes colorectal cancer cell growth through regulating the miR-497-5p/FOXK1 axis

Review

Cytotoxicity of synthetic derivatives against breast cancer and multi-drug resistant breast cancer cell lines: a literature-based perspective study

Primary research

IRF4 overexpression promotes the transdifferentiation of tregs into macrophage‐like cells to inhibit the development of colon cancer

Review

Ovarian cancer: epigenetics, drug resistance, and progression
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits