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Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression
The transcriptional regulator nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3) is constitutively activated in several cancer types and plays important roles in cancer development and progression. Heavily phosphorylated NFATc3 resides in the cytoplasm of resting cells, and dephosphorylated...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050899/ https://www.ncbi.nlm.nih.gov/pubmed/35484132 http://dx.doi.org/10.1038/s41419-022-04779-9 |
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author | Tong, Yingying Zhang, Zheng Cheng, Yurong Yang, Jing Fan, Cong Zhang, Xuyang Yang, Jiandong Wang, Li Guo, Dong Yan, Dong |
author_facet | Tong, Yingying Zhang, Zheng Cheng, Yurong Yang, Jing Fan, Cong Zhang, Xuyang Yang, Jiandong Wang, Li Guo, Dong Yan, Dong |
author_sort | Tong, Yingying |
collection | PubMed |
description | The transcriptional regulator nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3) is constitutively activated in several cancer types and plays important roles in cancer development and progression. Heavily phosphorylated NFATc3 resides in the cytoplasm of resting cells, and dephosphorylated NFATc3 translocates to the nucleus to activate expression of target genes in cells exposed to stimuli, for instance, hypoxia. Apart from phosphorylation, various post-translational modifications have been reported to regulate NFAT transcriptional activity. However, the mechanisms remain elusive. Here, we have demonstrated that NFATc3 is activated in human pancreatic ductal adenocarcinoma (PDAC) cells and that excessive activation of NFATc3 is correlated to advanced stages of PDAC and short survival time of PDAC patients. NFATc3 is deSUMOylated at K384 by SENP3 under hypoxia, which impairs the interaction between NFATc3 and phosphokinase GSK-3β, subsequently decreases NFATc3 phosphorylation and increases its nuclear occupancy. Knockdown of SENP3 greatly decreased hypoxia-induced NFATc3 nuclear occupancy. Our results highlight that SENP3-mediated deSUMOylation acts as an essential modulator of NFATc3, which is instrumental in PDAC tumor progression under hypoxia. |
format | Online Article Text |
id | pubmed-9050899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90508992022-04-30 Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression Tong, Yingying Zhang, Zheng Cheng, Yurong Yang, Jing Fan, Cong Zhang, Xuyang Yang, Jiandong Wang, Li Guo, Dong Yan, Dong Cell Death Dis Article The transcriptional regulator nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3) is constitutively activated in several cancer types and plays important roles in cancer development and progression. Heavily phosphorylated NFATc3 resides in the cytoplasm of resting cells, and dephosphorylated NFATc3 translocates to the nucleus to activate expression of target genes in cells exposed to stimuli, for instance, hypoxia. Apart from phosphorylation, various post-translational modifications have been reported to regulate NFAT transcriptional activity. However, the mechanisms remain elusive. Here, we have demonstrated that NFATc3 is activated in human pancreatic ductal adenocarcinoma (PDAC) cells and that excessive activation of NFATc3 is correlated to advanced stages of PDAC and short survival time of PDAC patients. NFATc3 is deSUMOylated at K384 by SENP3 under hypoxia, which impairs the interaction between NFATc3 and phosphokinase GSK-3β, subsequently decreases NFATc3 phosphorylation and increases its nuclear occupancy. Knockdown of SENP3 greatly decreased hypoxia-induced NFATc3 nuclear occupancy. Our results highlight that SENP3-mediated deSUMOylation acts as an essential modulator of NFATc3, which is instrumental in PDAC tumor progression under hypoxia. Nature Publishing Group UK 2022-04-28 /pmc/articles/PMC9050899/ /pubmed/35484132 http://dx.doi.org/10.1038/s41419-022-04779-9 Text en © The Author(s) 2022 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 Tong, Yingying Zhang, Zheng Cheng, Yurong Yang, Jing Fan, Cong Zhang, Xuyang Yang, Jiandong Wang, Li Guo, Dong Yan, Dong Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression |
title | Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression |
title_full | Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression |
title_fullStr | Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression |
title_full_unstemmed | Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression |
title_short | Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression |
title_sort | hypoxia-induced nfatc3 desumoylation enhances pancreatic carcinoma progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050899/ https://www.ncbi.nlm.nih.gov/pubmed/35484132 http://dx.doi.org/10.1038/s41419-022-04779-9 |
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