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METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway
The role of METTL3-mediated N6-methyladenosine (m(6)A) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673931/ https://www.ncbi.nlm.nih.gov/pubmed/38001065 http://dx.doi.org/10.1038/s41419-023-06287-w |
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author | Sun, Yuechao Gong, Weipeng Zhang, Song |
author_facet | Sun, Yuechao Gong, Weipeng Zhang, Song |
author_sort | Sun, Yuechao |
collection | PubMed |
description | The role of METTL3-mediated N6-methyladenosine (m(6)A) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited m(6)A on the 3’ untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which finally resulted in enhanced cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an m(6)A writer and a transcription regulator, which worked together in the same signaling pathway to drive colorectal cancer malignancy. |
format | Online Article Text |
id | pubmed-10673931 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106739312023-11-25 METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway Sun, Yuechao Gong, Weipeng Zhang, Song Cell Death Dis Article The role of METTL3-mediated N6-methyladenosine (m(6)A) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited m(6)A on the 3’ untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which finally resulted in enhanced cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an m(6)A writer and a transcription regulator, which worked together in the same signaling pathway to drive colorectal cancer malignancy. Nature Publishing Group UK 2023-11-25 /pmc/articles/PMC10673931/ /pubmed/38001065 http://dx.doi.org/10.1038/s41419-023-06287-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sun, Yuechao Gong, Weipeng Zhang, Song METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway |
title | METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway |
title_full | METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway |
title_fullStr | METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway |
title_full_unstemmed | METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway |
title_short | METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway |
title_sort | mettl3 promotes colorectal cancer progression through activating jak1/stat3 signaling pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673931/ https://www.ncbi.nlm.nih.gov/pubmed/38001065 http://dx.doi.org/10.1038/s41419-023-06287-w |
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