Methyltransferase-like proteins in cancer biology and potential therapeutic targeting

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Abstract

RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.

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Reading, writing and erasing mRNA methylation

Sara Zaccara, Ryan Ries, Samie R. Jaffrey (2019)

RNA methylation to form N6-methyladenosine (m6A) in mRNA accounts for the most abundant mRNA internal modification and has emerged as a widespread regulatory mechanism that controls gene expression in diverse physiological processes. Transcriptome-wide m6A mapping has revealed the distribution and pattern of m6A in cellular RNAs, referred to as the epitranscriptome. These maps have revealed the specific mRNAs that are regulated by m6A, providing mechanistic links connecting m6A to cellular differentiation, cancer progression and other processes. The effects of m6A on mRNA are mediated by an expanding list of m6A readers and m6A writer-complex components, as well as potential erasers that currently have unclear relevance to m6A prevalence in the transcriptome. Here we review new and emerging methods to characterize and quantify the epitranscriptome, and we discuss new concepts - in some cases, controversies - regarding our understanding of the mechanisms and functions of m6A readers, writers and erasers.

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The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells.

Shuibin Lin, Junho Choe, Peng Du … (2016)

METTL3 is an RNA methyltransferase implicated in mRNA biogenesis, decay, and translation control through N(6)-methyladenosine (m(6)A) modification. Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. In contrast to current models that invoke m(6)A reader proteins downstream of nuclear METTL3, we find METTL3 associates with ribosomes and promotes translation in the cytoplasm. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. METTL3 expression is elevated in lung adenocarcinoma and using both loss- and gain-of-function studies, we find that METTL3 promotes growth, survival, and invasion of human lung cancer cells. Our results uncover an important role of METTL3 in promoting translation of oncogenes in human lung cancer.

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RNA N6-methyladenosine methyltransferase METTL3 promotes liver cancer progression through YTHDF2 dependent post-transcriptional silencing of SOCS2.

Daniel Ho, Mengnuo Chen, Lai Wei … (2017)

Epigenetic alterations immensely contributed to human carcinogenesis. Conventional epigenetic studies predominantly focused on DNA methylation, histone modifications, and chromatin remodeling. Recently, diverse and reversible chemical modifications on RNAs emerge as a new layer of epigenetic regulation. N6-methyladenosine (m6A) is the most abundant chemical modification on eukaryotic mRNA and is important to the regulation of mRNA stability, splicing, and translation. Using transcriptome sequencing, we discovered that METTL3 (methyltransferase like 3), a major RNA N6-adenosine methyltransferase, was significantly up-regulated in human hepatocellular carcinoma (HCC) and multiple solid tumors. Clinically, overexpression of METTL3 was associated with poor prognosis of HCC patients. Functionally, we proved that knockdown of METTL3 drastically reduced HCC cell proliferation, migration and colony formation in vitro. Knockout of METTL3 remarkably suppressed HCC tumorigenicity and lung metastasis in vivo. On the other hand, using CRISPR/dCas9-VP64 activation system, we demonstrated that overexpression of METTL3 significantly promoted HCC growth both in vitro and in vivo. Through transcriptome sequencing, m6A-Seq and m6A MeRIP qRT-PCR, we identified SOCS2 (suppressor of cytokine signaling 2) as a target of METTL3-mediated m6A modification. Knockdown of METTL3 substantially abolished SOCS2 mRNA m6A modification and augmented SOCS2 mRNA expression. We also showed that m6A-mediated SOCS2 mRNA degradation relied on m6A "reader" protein YTHDF2 dependent pathway. In conclusion, we demonstrated that METTL3 was frequently up-regulated in human HCC and contributed to HCC progression. METTL3 repressed SOCS2 expression in HCC via the m6A-YTHDF2 dependent mechanism. Thus, our findings suggested a new dimension of epigenetic alteration in liver carcinogenesis. This article is protected by copyright. All rights reserved.

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Author and article information

Contributors

Pei Li: lipeifreemai@zzu.edu.cn

Zhi-Qiang Ling: lingzq@zjcc.org.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): 2 August 2023

Publication date PMC-release: 2 August 2023

Publication date Collection: 2023

Volume: 16

Electronic Location Identifier: 89

Affiliations

[1 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, Department of Pathophysiology, School of Basic Medical Sciences, , Zhengzhou University, ; Zhengzhou, 450052 P.R. China

[2 ]GRID grid.417397.f, ISNI 0000 0004 1808 0985, Zhejiang Cancer Institute, , Zhejiang Cancer Hospital, ; No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022 Zhejiang P.R. China

[3 ]GRID grid.9227.e, ISNI 0000000119573309, Hangzhou Institute of Medicine (HIM), , Chinese Academy of Sciences, ; Hangzhou, 310018 Zhejiang P.R. China

Article

Publisher ID: 1477

DOI: 10.1186/s13045-023-01477-7

PMC ID: 10394802

PubMed ID: 37533128

SO-VID: f5db28be-583e-4920-8b7d-b15415c775ec

License:

Open Access This 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 March 2023

Date accepted : 10 July 2023

Funding

Funded by: Zhejiang Medical and Health Science and Technology Project

Award ID: 2019ZD025

Award Recipient : Lian-Lian Hong

Funded by: Zhejiang Provincial Public Welfare Technology Research Plan Project

Award ID: LGD20H160003

Award Recipient : Lian-Lian Hong

Funded by: Program for Innovation Research Team (in Science and Technology) in University of Henan Province

Award ID: Grant No. 20IRTSTHN026

Award Recipient : Pei Li

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

Award ID: 81972908 and 32271238