METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/β-catenin signaling

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Abstract

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to radiation. Taken together, our results showed that LINC00839, modified by METTL3-mediated m6A, exerts tumor progression and radiation resistance by activating Wnt/β-catenin signaling.

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Most cited references 51

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m6A-dependent regulation of messenger RNA stability

Xiao Wang, Zhike Lu, Adrián Gómez-Brandón … (2013)

N6 -methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes 1,2 . Although essential to cell viability and development 3–5 , the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease 6–8 . Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies 9 . The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.

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Dynamic RNA Modifications in Gene Expression Regulation

Molly E Evans, Ian A Roundtree, Tao Pan … (2017)

Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.

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Unique features of long non-coding RNA biogenesis and function.

Jeffrey Quinn, Howard Y. Chang (2016)

Long non-coding RNAs (lncRNAs) are a diverse class of RNAs that engage in numerous biological processes across every branch of life. Although initially discovered as mRNA-like transcripts that do not encode proteins, recent studies have revealed features of lncRNAs that further distinguish them from mRNAs. In this Review, we describe special events in the lifetimes of lncRNAs - before, during and after transcription - and discuss how these events ultimately shape the unique characteristics and functional roles of lncRNAs.

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Author and article information

Contributors

Zhiliang Ding:

ORCID: http://orcid.org/0000-0002-4402-6646

zlding1970@163.com

Jing Ji:

ORCID: http://orcid.org/0000-0002-7372-024X

jijing@njmu.edu.cn

Xiefeng Wang:

ORCID: http://orcid.org/0000-0001-7031-5532

xiefeng@njmu.edu.cn

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 12 July 2023

Publication date PMC-release: 12 July 2023

Publication date Collection: July 2023

Volume: 14

Issue: 7

Electronic Location Identifier: 417

Affiliations

[1 ]GRID grid.440227.7, ISNI 0000 0004 1758 3572, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, ; Suzhou, Jiangsu 215006 China

[2 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, , Nanjing Medical University, ; Nanjing, Jiangsu 211166 China

[3 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, , Nanjing Medical University, ; Nanjing, Jiangsu 211166 China

[4 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Neurosurgery, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu 210029 China

[5 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Cancer Biology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[6 ]GRID grid.452509.f, ISNI 0000 0004 1764 4566, Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Institute of Cancer Research, ; Nanjing, Jiangsu 210009 China

Author information

Xu Qian http://orcid.org/0000-0003-1533-8568

Zhiliang Ding http://orcid.org/0000-0002-4402-6646

Jing Ji http://orcid.org/0000-0002-7372-024X

Xiefeng Wang http://orcid.org/0000-0001-7031-5532

Article

Publisher ID: 5933

DOI: 10.1038/s41419-023-05933-7

PMC ID: 10338500

PubMed ID: 37438359

SO-VID: b77a2372-34fb-41d2-bacf-850ef48f30dc

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 December 2022

Date revision received : 11 May 2023

Date accepted : 27 June 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82172667

Award Recipient : Xiefeng Wang

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ScienceOpen disciplines: Cell biology

Keywords: cns cancer,long non-coding rnas

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ScienceOpen disciplines: Cell biology

Keywords: cns cancer, long non-coding rnas

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METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/β-catenin signaling

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Abstract

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GLUT4 biology

Most cited references 51

m6A-dependent regulation of messenger RNA stability

Dynamic RNA Modifications in Gene Expression Regulation

Unique features of long non-coding RNA biogenesis and function.

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