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C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer

C1GALT1 controls the crucial step of GalNAc-type O-glycosylation and is associated with both physiologic and pathologic conditions, including cancers. EPH receptors comprise the largest family of receptor tyrosine kinases (RTKs) and modulate a diverse range of developmental processes and human disea...

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Autores principales: Lee, Po-Chu, Chen, Syue-Ting, Kuo, Ting-Chun, Lin, Tzu-Chi, Lin, Mei-Chun, Huang, John, Hung, Ji-Shiang, Hsu, Chia-Lang, Juan, Hsueh-Fen, Lee, Po-Huang, Huang, Min-Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098884/
https://www.ncbi.nlm.nih.gov/pubmed/32005975
http://dx.doi.org/10.1038/s41388-020-1178-7
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author Lee, Po-Chu
Chen, Syue-Ting
Kuo, Ting-Chun
Lin, Tzu-Chi
Lin, Mei-Chun
Huang, John
Hung, Ji-Shiang
Hsu, Chia-Lang
Juan, Hsueh-Fen
Lee, Po-Huang
Huang, Min-Chuan
author_facet Lee, Po-Chu
Chen, Syue-Ting
Kuo, Ting-Chun
Lin, Tzu-Chi
Lin, Mei-Chun
Huang, John
Hung, Ji-Shiang
Hsu, Chia-Lang
Juan, Hsueh-Fen
Lee, Po-Huang
Huang, Min-Chuan
author_sort Lee, Po-Chu
collection PubMed
description C1GALT1 controls the crucial step of GalNAc-type O-glycosylation and is associated with both physiologic and pathologic conditions, including cancers. EPH receptors comprise the largest family of receptor tyrosine kinases (RTKs) and modulate a diverse range of developmental processes and human diseases. However, the role of C1GALT1 in the signaling of EPH receptors remains largely overlooked. Here, we showed that C1GALT1 high expression in gastric adenocarcinomas correlated with adverse clinicopathologic features and is an independent prognostic factor for poor overall survival. Silencing or loss of C1GALT1 inhibited cell viability, migration, invasion, tumor growth and metastasis, as well as increased apoptosis and cytotoxicity of 5-fluorouracil in AGS and MKN45 cells. Phospho-RTK array and western blot analysis showed that C1GALT1 depletion suppressed tyrosine phosphorylation of EPHA2 induced by soluble Ephrin A1-Fc. O-glycans on EPHA2 were modified by C1GALT1 and both S277A and T429A mutants, which are O-glycosites on EPHA2, dramatically enhanced phosphorylation of Y588, suggesting that not only overall O-glycan structures but also site-specific O-glycosylation can regulate EPHA2 activity. Furthermore, depletion of C1GALT1 decreased Ephrin A1-Fc induced migration and reduced Ephrin A1 binding to cell surfaces. The effects of C1GALT1 knockdown or knockout on cell invasiveness in vitro and in vivo were phenocopied by EPHA2 knockdown in gastric cancer cells. These results suggest that C1GALT1 promotes phosphorylation of EPHA2 and enhances soluble Ephrin A1-mediated migration primarily by modifying EPHA2 O-glycosylation. Our study highlights the importance of GalNAc-type O-glycosylation in EPH receptor-regulated diseases and identifies C1GALT1 as a potential therapeutic target for gastric cancer.
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spelling pubmed-70988842020-03-30 C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer Lee, Po-Chu Chen, Syue-Ting Kuo, Ting-Chun Lin, Tzu-Chi Lin, Mei-Chun Huang, John Hung, Ji-Shiang Hsu, Chia-Lang Juan, Hsueh-Fen Lee, Po-Huang Huang, Min-Chuan Oncogene Article C1GALT1 controls the crucial step of GalNAc-type O-glycosylation and is associated with both physiologic and pathologic conditions, including cancers. EPH receptors comprise the largest family of receptor tyrosine kinases (RTKs) and modulate a diverse range of developmental processes and human diseases. However, the role of C1GALT1 in the signaling of EPH receptors remains largely overlooked. Here, we showed that C1GALT1 high expression in gastric adenocarcinomas correlated with adverse clinicopathologic features and is an independent prognostic factor for poor overall survival. Silencing or loss of C1GALT1 inhibited cell viability, migration, invasion, tumor growth and metastasis, as well as increased apoptosis and cytotoxicity of 5-fluorouracil in AGS and MKN45 cells. Phospho-RTK array and western blot analysis showed that C1GALT1 depletion suppressed tyrosine phosphorylation of EPHA2 induced by soluble Ephrin A1-Fc. O-glycans on EPHA2 were modified by C1GALT1 and both S277A and T429A mutants, which are O-glycosites on EPHA2, dramatically enhanced phosphorylation of Y588, suggesting that not only overall O-glycan structures but also site-specific O-glycosylation can regulate EPHA2 activity. Furthermore, depletion of C1GALT1 decreased Ephrin A1-Fc induced migration and reduced Ephrin A1 binding to cell surfaces. The effects of C1GALT1 knockdown or knockout on cell invasiveness in vitro and in vivo were phenocopied by EPHA2 knockdown in gastric cancer cells. These results suggest that C1GALT1 promotes phosphorylation of EPHA2 and enhances soluble Ephrin A1-mediated migration primarily by modifying EPHA2 O-glycosylation. Our study highlights the importance of GalNAc-type O-glycosylation in EPH receptor-regulated diseases and identifies C1GALT1 as a potential therapeutic target for gastric cancer. Nature Publishing Group UK 2020-01-31 2020 /pmc/articles/PMC7098884/ /pubmed/32005975 http://dx.doi.org/10.1038/s41388-020-1178-7 Text en © The Author(s) 2020 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/.
spellingShingle Article
Lee, Po-Chu
Chen, Syue-Ting
Kuo, Ting-Chun
Lin, Tzu-Chi
Lin, Mei-Chun
Huang, John
Hung, Ji-Shiang
Hsu, Chia-Lang
Juan, Hsueh-Fen
Lee, Po-Huang
Huang, Min-Chuan
C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer
title C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer
title_full C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer
title_fullStr C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer
title_full_unstemmed C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer
title_short C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer
title_sort c1galt1 is associated with poor survival and promotes soluble ephrin a1-mediated cell migration through activation of epha2 in gastric cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098884/
https://www.ncbi.nlm.nih.gov/pubmed/32005975
http://dx.doi.org/10.1038/s41388-020-1178-7
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