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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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