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SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma

Tumour cells mainly generate energy from glycolysis, which is commonly coupled with lactate production even under normoxic conditions. As a critical lactate transporter, monocarboxylate transporter 4 (MCT4) is highly expressed in glycolytic tissues, such as muscles and tumours. Overexpression of MCT...

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Autores principales: Zhao, Meng, Huang, Chen, Yang, Lexin, Pan, Boyu, Yang, Shuting, Chang, Jiao, Jin, Yu, Zhao, Gang, Yue, Dongsheng, Qie, Shuo, Ren, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10564934/
https://www.ncbi.nlm.nih.gov/pubmed/37816756
http://dx.doi.org/10.1038/s41419-023-06208-x
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author Zhao, Meng
Huang, Chen
Yang, Lexin
Pan, Boyu
Yang, Shuting
Chang, Jiao
Jin, Yu
Zhao, Gang
Yue, Dongsheng
Qie, Shuo
Ren, Li
author_facet Zhao, Meng
Huang, Chen
Yang, Lexin
Pan, Boyu
Yang, Shuting
Chang, Jiao
Jin, Yu
Zhao, Gang
Yue, Dongsheng
Qie, Shuo
Ren, Li
author_sort Zhao, Meng
collection PubMed
description Tumour cells mainly generate energy from glycolysis, which is commonly coupled with lactate production even under normoxic conditions. As a critical lactate transporter, monocarboxylate transporter 4 (MCT4) is highly expressed in glycolytic tissues, such as muscles and tumours. Overexpression of MCT4 is associated with poor prognosis for patients with various tumours. However, how MCT4 function is post-translationally regulated remains largely unknown. Taking advantage of human lung adenocarcinoma (LUAD) cells, this study revealed that MCT4 can be polyubiquitylated in a nonproteolytic manner by SYVN1 E3 ubiquitin ligase. The polyubiquitylation facilitates the localization of MCT4 into the plasma membrane, which improves lactate export by MCT4; in accordance, metabolism characterized by reduced glycolysis and lactate production is effectively reprogrammed by SYVN1 knockdown, which can be reversed by MCT4 overexpression. Biologically, SYVN1 knockdown successfully compromises cell proliferation and tumour xenograft growth in mouse models that can be partially rescued by overexpression of MCT4. Clinicopathologically, overexpression of SYVN1 is associated with poor prognosis in patients with LUAD, highlighting the importance of the SYVN1-MCT4 axis, which performs metabolic reprogramming during the progression of LUAD.
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spelling pubmed-105649342023-10-12 SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma Zhao, Meng Huang, Chen Yang, Lexin Pan, Boyu Yang, Shuting Chang, Jiao Jin, Yu Zhao, Gang Yue, Dongsheng Qie, Shuo Ren, Li Cell Death Dis Article Tumour cells mainly generate energy from glycolysis, which is commonly coupled with lactate production even under normoxic conditions. As a critical lactate transporter, monocarboxylate transporter 4 (MCT4) is highly expressed in glycolytic tissues, such as muscles and tumours. Overexpression of MCT4 is associated with poor prognosis for patients with various tumours. However, how MCT4 function is post-translationally regulated remains largely unknown. Taking advantage of human lung adenocarcinoma (LUAD) cells, this study revealed that MCT4 can be polyubiquitylated in a nonproteolytic manner by SYVN1 E3 ubiquitin ligase. The polyubiquitylation facilitates the localization of MCT4 into the plasma membrane, which improves lactate export by MCT4; in accordance, metabolism characterized by reduced glycolysis and lactate production is effectively reprogrammed by SYVN1 knockdown, which can be reversed by MCT4 overexpression. Biologically, SYVN1 knockdown successfully compromises cell proliferation and tumour xenograft growth in mouse models that can be partially rescued by overexpression of MCT4. Clinicopathologically, overexpression of SYVN1 is associated with poor prognosis in patients with LUAD, highlighting the importance of the SYVN1-MCT4 axis, which performs metabolic reprogramming during the progression of LUAD. Nature Publishing Group UK 2023-10-10 /pmc/articles/PMC10564934/ /pubmed/37816756 http://dx.doi.org/10.1038/s41419-023-06208-x 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
Zhao, Meng
Huang, Chen
Yang, Lexin
Pan, Boyu
Yang, Shuting
Chang, Jiao
Jin, Yu
Zhao, Gang
Yue, Dongsheng
Qie, Shuo
Ren, Li
SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma
title SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma
title_full SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma
title_fullStr SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma
title_full_unstemmed SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma
title_short SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma
title_sort syvn1-mediated ubiquitylation directs localization of mct4 in the plasma membrane to promote the progression of lung adenocarcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10564934/
https://www.ncbi.nlm.nih.gov/pubmed/37816756
http://dx.doi.org/10.1038/s41419-023-06208-x
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