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A novel mechanism for C1GALT1 in the regulation of gastric cancer progression
BACKGROUND: Gastric cancer (GC) is a highly aggressive and lethal disease around the world. High expression of core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), the primary enzyme responsible for protein O-glycosylation, plays a critical role in gastric carcinogenesis. However, proteins that can be O...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393437/ https://www.ncbi.nlm.nih.gov/pubmed/34452648 http://dx.doi.org/10.1186/s13578-021-00678-2 |
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author | Dong, Xiaoxia Chen, Chunli Deng, Xinzhou Liu, Yongyu Duan, Qiwen Peng, Zhen Luo, Zhiguo Shen, Li |
author_facet | Dong, Xiaoxia Chen, Chunli Deng, Xinzhou Liu, Yongyu Duan, Qiwen Peng, Zhen Luo, Zhiguo Shen, Li |
author_sort | Dong, Xiaoxia |
collection | PubMed |
description | BACKGROUND: Gastric cancer (GC) is a highly aggressive and lethal disease around the world. High expression of core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), the primary enzyme responsible for protein O-glycosylation, plays a critical role in gastric carcinogenesis. However, proteins that can be O-glycosylated by C1GALT1 in GC have not been completely elucidated. Also, the mechanism leading to its upregulation in GC is currently unknown. RESULTS: Using public databases and our patient samples, we confirmed that C1GALT1 expression was upregulated at both the mRNA and protein levels in GC tissues. Elevated expression of C1GALT1 protein was closely associated with advanced TNM stage, lymph node metastasis, tumor recurrence, and poor overall survival. With gain- and loss-of-function approaches, we demonstrated that C1GALT1 promoted GC cell proliferation, migration, and invasion. By employing lectin pull-down assay and mass spectrometry, integrin α5 was identified as a new downstream target of C1GALT1 in GC. C1GALT1 was able to modify O-linked glycosylation on integrin α5 and thereby modulate the activation of the PI3K/AKT pathway. Functional experiments indicated that integrin α5 inhibition could reverse C1GALT1-mediated tumor growth and metastasis both in vitro and in vivo. Moreover, transcription factor SP1 was found to bind to the C1GALT1 promoter region and activated its expression. Further investigation proved that miR-152 negatively regulated C1GALT1 expression by directly binding to its 3′ -UTR. CONCLUSIONS: Our findings uncover a novel mechanism for C1GALT1 in the regulation of GC progression. Thus, C1GALT1 may serve as a promising target for the diagnosis and treatment of GC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-021-00678-2. |
format | Online Article Text |
id | pubmed-8393437 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-83934372021-08-27 A novel mechanism for C1GALT1 in the regulation of gastric cancer progression Dong, Xiaoxia Chen, Chunli Deng, Xinzhou Liu, Yongyu Duan, Qiwen Peng, Zhen Luo, Zhiguo Shen, Li Cell Biosci Research BACKGROUND: Gastric cancer (GC) is a highly aggressive and lethal disease around the world. High expression of core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), the primary enzyme responsible for protein O-glycosylation, plays a critical role in gastric carcinogenesis. However, proteins that can be O-glycosylated by C1GALT1 in GC have not been completely elucidated. Also, the mechanism leading to its upregulation in GC is currently unknown. RESULTS: Using public databases and our patient samples, we confirmed that C1GALT1 expression was upregulated at both the mRNA and protein levels in GC tissues. Elevated expression of C1GALT1 protein was closely associated with advanced TNM stage, lymph node metastasis, tumor recurrence, and poor overall survival. With gain- and loss-of-function approaches, we demonstrated that C1GALT1 promoted GC cell proliferation, migration, and invasion. By employing lectin pull-down assay and mass spectrometry, integrin α5 was identified as a new downstream target of C1GALT1 in GC. C1GALT1 was able to modify O-linked glycosylation on integrin α5 and thereby modulate the activation of the PI3K/AKT pathway. Functional experiments indicated that integrin α5 inhibition could reverse C1GALT1-mediated tumor growth and metastasis both in vitro and in vivo. Moreover, transcription factor SP1 was found to bind to the C1GALT1 promoter region and activated its expression. Further investigation proved that miR-152 negatively regulated C1GALT1 expression by directly binding to its 3′ -UTR. CONCLUSIONS: Our findings uncover a novel mechanism for C1GALT1 in the regulation of GC progression. Thus, C1GALT1 may serve as a promising target for the diagnosis and treatment of GC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-021-00678-2. BioMed Central 2021-08-26 /pmc/articles/PMC8393437/ /pubmed/34452648 http://dx.doi.org/10.1186/s13578-021-00678-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Dong, Xiaoxia Chen, Chunli Deng, Xinzhou Liu, Yongyu Duan, Qiwen Peng, Zhen Luo, Zhiguo Shen, Li A novel mechanism for C1GALT1 in the regulation of gastric cancer progression |
title | A novel mechanism for C1GALT1 in the regulation of gastric cancer progression |
title_full | A novel mechanism for C1GALT1 in the regulation of gastric cancer progression |
title_fullStr | A novel mechanism for C1GALT1 in the regulation of gastric cancer progression |
title_full_unstemmed | A novel mechanism for C1GALT1 in the regulation of gastric cancer progression |
title_short | A novel mechanism for C1GALT1 in the regulation of gastric cancer progression |
title_sort | novel mechanism for c1galt1 in the regulation of gastric cancer progression |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393437/ https://www.ncbi.nlm.nih.gov/pubmed/34452648 http://dx.doi.org/10.1186/s13578-021-00678-2 |
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