Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
28 04 2022
28 04 2022
Historique:
received:
21
06
2021
accepted:
21
03
2022
revised:
01
03
2022
entrez:
28
4
2022
pubmed:
29
4
2022
medline:
3
5
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35484132
doi: 10.1038/s41419-022-04779-9
pii: 10.1038/s41419-022-04779-9
pmc: PMC9050899
doi:
Substances chimiques
NFATC Transcription Factors
0
NFATC3 protein, human
0
transcription factor NF-AT c3
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Cysteine Endopeptidases
EC 3.4.22.-
SENP3 protein, human
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
413Informations de copyright
© 2022. The Author(s).
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