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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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

Journal

Journal ID (iso-abbrev): Mol Cancer

Title: Molecular cancer

Publisher: Springer Science and Business Media LLC

ISSN (Electronic): 1476-4598

ISSN (Print): 1476-4598

Publication date (Electronic): Jan 28 2022

Volume: 21

Issue: 1

Affiliations

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

[2 ] The First Affiliated Hospital, Department of Rheumatology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.

[3 ] 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 ] 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.

[6 ] 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. jingliucsu@hotmail.com.

[7 ] Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, Guangdong, China. zhang_ji001@hotmail.com.

[8 ] The First Affiliated Hospital, Department of Rheumatology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. zhang_ji001@hotmail.com.

Article

Publisher Item ID: 10.1186/s12943-022-01508-w

DOI: 10.1186/s12943-022-01508-w

PMC ID: 8796496

PubMed ID: 35090469

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

History

Keywords: Necroptosis,Apoptosis,Autophagy,Cancer,Ferroptosis,N6-methyladenosine,Pyroptosis

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Keywords: Necroptosis, Apoptosis, Autophagy, Cancer, Ferroptosis, N6-methyladenosine, Pyroptosis

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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