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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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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. |
format | Online Article Text |
id | pubmed-10265050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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