METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury

The biological roles of epithelial–mesenchymal transition (EMT) in the pathogenesis of radiation‐induced lung injury (RILI) have been widely demonstrated, but the mechanisms involved have been incompletely elucidated. N(6)‐methyladenosine (m(6)A) modification, the most abundant reversible methylatio...

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Autores principales: Feng, Yang, Yuan, Ping, Guo, Hongjuan, Gu, Liming, Yang, Zhao, Wang, Jian, Zhu, Wei, Zhang, Qi, Cao, Jianping, Wang, Lili, Jiao, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265050/
https://www.ncbi.nlm.nih.gov/pubmed/37072646
http://dx.doi.org/10.1002/advs.202204784
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author Feng, Yang
Yuan, Ping
Guo, Hongjuan
Gu, Liming
Yang, Zhao
Wang, Jian
Zhu, Wei
Zhang, Qi
Cao, Jianping
Wang, Lili
Jiao, Yang
author_facet Feng, Yang
Yuan, Ping
Guo, Hongjuan
Gu, Liming
Yang, Zhao
Wang, Jian
Zhu, Wei
Zhang, Qi
Cao, Jianping
Wang, Lili
Jiao, Yang
author_sort Feng, Yang
collection PubMed
description The biological roles of epithelial–mesenchymal transition (EMT) in the pathogenesis of radiation‐induced lung injury (RILI) have been widely demonstrated, but the mechanisms involved have been incompletely elucidated. N(6)‐methyladenosine (m(6)A) modification, the most abundant reversible methylation modification in eukaryotic mRNAs, plays vital roles in multiple biological processes. Whether and how m(6)A modification participates in ionizing radiation (IR)‐induced EMT and RILI remain unclear. Here, significantly increased m(6)A levels upon IR‐induced EMT are detected both in vivo and in vitro. Furthermore, upregulated methyltransferase‐like 3 (METTL3) expression and downregulated α‐ketoglutarate‐dependent dioxygenase AlkB homolog 5 (ALKBH5) expression are detected. In addition, blocking METTL3‐mediated m(6)A modification suppresses IR‐induced EMT both in vivo and in vitro. Mechanistically, forkhead box O1 (FOXO1) is identified as a key target of METTL3 by a methylated RNA immunoprecipitation (MeRIP) assay. FOXO1 expression is downregulated by METTL3‐mediated mRNA m(6)A modification in a YTH‐domain family 2 (YTHDF2)‐dependent manner, which subsequently activates the AKT and ERK signaling pathways. Overall, the present study shows that IR‐responsive METTL3 is involved in IR‐induced EMT, probably by activating the AKT and ERK signaling pathways via YTHDF2‐dependent FOXO1 m(6)A modification, which may be a novel mechanism involved in the occurrence and development of RILI.
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spelling pubmed-102650502023-06-15 METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury Feng, Yang Yuan, Ping Guo, Hongjuan Gu, Liming Yang, Zhao Wang, Jian Zhu, Wei Zhang, Qi Cao, Jianping Wang, Lili Jiao, Yang Adv Sci (Weinh) Research Articles The biological roles of epithelial–mesenchymal transition (EMT) in the pathogenesis of radiation‐induced lung injury (RILI) have been widely demonstrated, but the mechanisms involved have been incompletely elucidated. N(6)‐methyladenosine (m(6)A) modification, the most abundant reversible methylation modification in eukaryotic mRNAs, plays vital roles in multiple biological processes. Whether and how m(6)A modification participates in ionizing radiation (IR)‐induced EMT and RILI remain unclear. Here, significantly increased m(6)A levels upon IR‐induced EMT are detected both in vivo and in vitro. Furthermore, upregulated methyltransferase‐like 3 (METTL3) expression and downregulated α‐ketoglutarate‐dependent dioxygenase AlkB homolog 5 (ALKBH5) expression are detected. In addition, blocking METTL3‐mediated m(6)A modification suppresses IR‐induced EMT both in vivo and in vitro. Mechanistically, forkhead box O1 (FOXO1) is identified as a key target of METTL3 by a methylated RNA immunoprecipitation (MeRIP) assay. FOXO1 expression is downregulated by METTL3‐mediated mRNA m(6)A modification in a YTH‐domain family 2 (YTHDF2)‐dependent manner, which subsequently activates the AKT and ERK signaling pathways. Overall, the present study shows that IR‐responsive METTL3 is involved in IR‐induced EMT, probably by activating the AKT and ERK signaling pathways via YTHDF2‐dependent FOXO1 m(6)A modification, which may be a novel mechanism involved in the occurrence and development of RILI. John Wiley and Sons Inc. 2023-04-18 /pmc/articles/PMC10265050/ /pubmed/37072646 http://dx.doi.org/10.1002/advs.202204784 Text en © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Feng, Yang
Yuan, Ping
Guo, Hongjuan
Gu, Liming
Yang, Zhao
Wang, Jian
Zhu, Wei
Zhang, Qi
Cao, Jianping
Wang, Lili
Jiao, Yang
METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury
title METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury
title_full METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury
title_fullStr METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury
title_full_unstemmed METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury
title_short METTL3 Mediates Epithelial–Mesenchymal Transition by Modulating FOXO1 mRNA N(6)‐Methyladenosine‐Dependent YTHDF2 Binding: A Novel Mechanism of Radiation‐Induced Lung Injury
title_sort mettl3 mediates epithelial–mesenchymal transition by modulating foxo1 mrna n(6)‐methyladenosine‐dependent ythdf2 binding: a novel mechanism of radiation‐induced lung injury
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265050/
https://www.ncbi.nlm.nih.gov/pubmed/37072646
http://dx.doi.org/10.1002/advs.202204784
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