Insights into N6-methyladenosine and programmed cell death in cancer

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Abstract

N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.

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Most cited references 141

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Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.

Dan Dominissini, Sharon Moshitch-Moshkovitz, Schraga Schwartz … (2012)

An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.

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N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

Guifang Jia, Ye Fu, Xu Zhao … (2011)

We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.

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N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

Xiao Wang, Boxuan Simen Zhao, Ian A Roundtree … (2015)

N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A-modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.

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Author and article information

Contributors

Jing Liu: jingliucsu@hotmail.com

Ji Zhang:

ORCID: http://orcid.org/0000-0002-6610-9805

zhang_ji001@hotmail.com

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): 28 January 2022

Publication date PMC-release: 28 January 2022

Publication date Collection: 2022

Volume: 21

Electronic Location Identifier: 32

Affiliations

[1 ]Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033 Guangdong China

[2 ]GRID grid.412017.1, ISNI 0000 0001 0266 8918, The First Affiliated Hospital, Department of Rheumatology, , Hengyang Medical School, University of South China, ; Hengyang, 421001 Hunan China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Hunan Province Key Laboratory of Basic and Applied Hematology, Molecular Biology Research Center & Center for Medical Genetics, , School of Life Sciences, Central South University, ; Changsha, 410078 Hunan China

[4 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, Department of Dermatology, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Clinical Research Center for Cancer Immunotherapy, , Xiangya Hospital, Central South University, ; Changsha, 410008 Hunan China

[5 ]The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South Chinal, Hengyang, 421001 Hunan China

Author information

Ji Zhang http://orcid.org/0000-0002-6610-9805

Article

Publisher ID: 1508

DOI: 10.1186/s12943-022-01508-w

PMC ID: 8796496

PubMed ID: 35090469

SO-VID: 02ec83e2-d38f-4ef1-bd14-e1c0c5c1521c

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 : 29 August 2021

Date accepted : 12 January 2022

Funding

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

Award ID: 82170138

Award ID: 81870105

Award ID: 81920108004

Award ID: 81770107

Award Recipient : Hui Li Jing Liu Ji Zhang

Funded by: FundRef http://dx.doi.org/10.13039/501100004735, Natural Science Foundation of Hunan Province;

Award ID: 2021JJ30022

Award ID: 2019JJ20014

Award Recipient : Jing Zhong Ji Zhang

Funded by: Scientific Research Fund Project of Hunan Provincial Health Commission

Award ID: 20201921

Award Recipient : Ji Zhang

Funded by: National Key Research and Development Program of China

Award ID: 2018YFA0107800

Award Recipient : Jing Liu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: n6-methyladenosine,cancer,apoptosis,autophagy,pyroptosis,ferroptosis,necroptosis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: n6-methyladenosine, cancer, apoptosis, autophagy, pyroptosis, ferroptosis, necroptosis

Insights into N6-methyladenosine and programmed cell death in cancer

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Karger: Oncology

Most cited references 141

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.

N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

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