Functions of N6-methyladenosine and its role in cancer

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Abstract

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

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Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis

Yueshuai Guo, Chuan Sheng He, Bin Shen … (2017)

N 6 -methyladenosine (m 6 A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m 6 A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m 6 A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m 6 A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m 6 A-binding protein that plays critical roles during spermatogenesis.

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VIRMA mediates preferential m 6 A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation

Yanan Yue, Jun Liu, Xiaolong Cui … (2018)

N 6-methyladenosine (m6A) is enriched in 3′untranslated region (3′UTR) and near stop codon of mature polyadenylated mRNAs in mammalian systems and has regulatory roles in eukaryotic mRNA transcriptome switch. Significantly, the mechanism for this modification preference remains unknown, however. Herein we report a characterization of the full m6A methyltransferase complex in HeLa cells identifying METTL3/METTL14/WTAP/VIRMA/HAKAI/ZC3H13 as the key components, and we show that VIRMA mediates preferential mRNA methylation in 3′UTR and near stop codon. Biochemical studies reveal that VIRMA recruits the catalytic core components METTL3/METTL14/WTAP to guide region-selective methylations. Around 60% of VIRMA mRNA immunoprecipitation targets manifest strong m6A enrichment in 3′UTR. Depletions of VIRMA and METTL3 induce 3′UTR lengthening of several hundred mRNAs with over 50% targets in common. VIRMA associates with polyadenylation cleavage factors CPSF5 and CPSF6 in an RNA-dependent manner. Depletion of CPSF5 leads to significant shortening of 3′UTR of over 2800 mRNAs, 84% of which are modified with m6A and have increased m6A peak density in 3′UTR and near stop codon after CPSF5 knockdown. Together, our studies provide insights into m6A deposition specificity in 3′UTR and its correlation with alternative polyadenylation.

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METTL3 facilitates tumor progression via an m 6 A-IGF2BP2-dependent mechanism in colorectal carcinoma

Ting Li, Pei-Shan Hu, Zhixiang Zuo … (2019)

Background Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. Methods Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. Results Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including “writer”, “reader”, and “target”, exhibited a better prognostic value for CRC patients than any of these components individually. Conclusions Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1038-7) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Gang Yin:

ORCID: http://orcid.org/0000-0003-3753-0753

gangyin@csu.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 4 December 2019

Publication date PMC-release: 4 December 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 176

Affiliations

[1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, , Central South University, ; Changsha, 410008 Hunan Province China

[2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, School of Basic Medical Sciences, , Central South University, ; Changsha, 410013 Hunan Province China

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Gang Yin http://orcid.org/0000-0003-3753-0753

Article

Publisher ID: 1109

DOI: 10.1186/s12943-019-1109-9

PMC ID: 6892141

PubMed ID: 31801551

SO-VID: 18b3d9f1-1bd7-4ad6-8d64-1a30524b018e

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 July 2019

Date accepted : 25 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: No. 81572900

Award Recipient : Gang Yin

Funded by: The Fundamental Research Funds for the Central Universities of Central South University

Award ID: No. 1053320171187 and No. 2018zzts232

Award Recipient : Gang Yin

Funded by: The Undergraduate Training Programs for Innovation and Entrepreneurship

Award ID: UTPIE, XCX20190537

Award Recipient : Liuer He

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: n6-methyladenosine,writer,eraser,reader,cancer

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: n6-methyladenosine, writer, eraser, reader, cancer

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Most cited references 71

Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis

VIRMA mediates preferential m 6 A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation

METTL3 facilitates tumor progression via an m 6 A-IGF2BP2-dependent mechanism in colorectal carcinoma

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