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METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding
The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and the...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217513/ https://www.ncbi.nlm.nih.gov/pubmed/34155197 http://dx.doi.org/10.1038/s41467-021-23501-5 |
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author | Wang, Wei Shao, Fei Yang, Xueying Wang, Juhong Zhu, Rongxuan Yang, Yannan Zhao, Gaoxiang Guo, Dong Sun, Yingli Wang, Jie Xue, Qi Gao, Shugeng Gao, Yibo He, Jie Lu, Zhimin |
author_facet | Wang, Wei Shao, Fei Yang, Xueying Wang, Juhong Zhu, Rongxuan Yang, Yannan Zhao, Gaoxiang Guo, Dong Sun, Yingli Wang, Jie Xue, Qi Gao, Shugeng Gao, Yibo He, Jie Lu, Zhimin |
author_sort | Wang, Wei |
collection | PubMed |
description | The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. m(6)A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m(6)A modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC. |
format | Online Article Text |
id | pubmed-8217513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82175132021-07-09 METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding Wang, Wei Shao, Fei Yang, Xueying Wang, Juhong Zhu, Rongxuan Yang, Yannan Zhao, Gaoxiang Guo, Dong Sun, Yingli Wang, Jie Xue, Qi Gao, Shugeng Gao, Yibo He, Jie Lu, Zhimin Nat Commun Article The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. m(6)A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m(6)A modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC. Nature Publishing Group UK 2021-06-21 /pmc/articles/PMC8217513/ /pubmed/34155197 http://dx.doi.org/10.1038/s41467-021-23501-5 Text en © The Author(s) 2021, corrected publication 2021 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 Wang, Wei Shao, Fei Yang, Xueying Wang, Juhong Zhu, Rongxuan Yang, Yannan Zhao, Gaoxiang Guo, Dong Sun, Yingli Wang, Jie Xue, Qi Gao, Shugeng Gao, Yibo He, Jie Lu, Zhimin METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding |
title | METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding |
title_full | METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding |
title_fullStr | METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding |
title_full_unstemmed | METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding |
title_short | METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding |
title_sort | mettl3 promotes tumour development by decreasing apc expression mediated by apc mrna n(6)-methyladenosine-dependent ythdf binding |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217513/ https://www.ncbi.nlm.nih.gov/pubmed/34155197 http://dx.doi.org/10.1038/s41467-021-23501-5 |
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