Roles of METTL3 in cancer: mechanisms and therapeutic targeting

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Abstract

N ⁶-methyladenosine (m ⁶A) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its m ⁶A RNA methyltransferase activity. While the roles of m ⁶A modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The well-documented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.

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m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

Huilin Huang, Hengyou Weng, Jianjun Chen (2020)

N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting m6A regulators for cancer therapy.

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Molecular genetics of colorectal cancer.

Eric R. Fearon (2011)

Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes-most prominently the APC, KRAS, and p53 genes-are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.

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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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Author and article information

Contributors

Yangqiu Li: yangqiuli@hotmail.com

Hengyou Weng: weng_hengyou@grmh-gdl.cn

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 27 August 2020

Publication date PMC-release: 27 August 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 117

Affiliations

[1 ]Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005 China

[2 ]GRID grid.258164.c, ISNI 0000 0004 1790 3548, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, , Jinan University, ; Guangzhou, 510632 China

[3 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, The Fifth Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510700 China

[4 ]GRID grid.9227.e, ISNI 0000000119573309, Guangzhou Institutes of Biomedicine and Health, , Chinese Academy of Sciences, ; Guangzhou, 510530 China

Author information

Wanxu Huang http://orcid.org/0000-0002-9159-3678

Article

Publisher ID: 951

DOI: 10.1186/s13045-020-00951-w

PMC ID: 7457244

PubMed ID: 32854717

SO-VID: bec17e06-cbeb-481b-956c-d72f8ea17eef

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

History

Date received : 10 June 2020

Date accepted : 17 August 2020

Funding

Funded by: GRMH-GDL Start-up Research Grant

Award ID: 1101201204

Award Recipient : Hengyou Weng

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

Award ID: 81770158

Award Recipient : Chengwu Zeng

Funded by: Pearl River S&T Nova Program of Guangzhou

Award ID: 201906010002

Award Recipient : Chengwu Zeng

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: rna modification,mettl3,m6a,cancer,non-coding rna,drug discovery

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: rna modification, mettl3, m6a, cancer, non-coding rna, drug discovery

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Roles of METTL3 in cancer: mechanisms and therapeutic targeting

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Most cited references 65

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

Molecular genetics of colorectal cancer.

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

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