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Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression.

ABSTRACT: 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.

SUBMITTER: Tong Y

PROVIDER: S-EPMC9050899 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression.

Tong Yingying Y Zhang Zheng Z Cheng Yurong Y Yang Jing J Fan Cong C Zhang Xuyang X Yang Jiandong J Wang Li L Guo Dong D Yan Dong D

Cell death & disease 20220428 4

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 ...[more]

PMID: 35484132

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Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression.

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Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression.

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