Phosphorylation at Ser10 triggered p27 degradation and promoted gallbladder carcinoma cell migration and invasion by regulating stathmin1 under glucose deficiency

Gallbladder carcinoma (GBC) is a considerable challenge because of its high metastatic potential. The tumor microenvironment is characterized by nutrient starvation, which promotes tumor metastasis. Stathmin1, an important microtubuleregulating protein, is overexpressed and promotes metastasis in GB...

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Bibliographic Details
Published in:Cellular signalling 2021-04, Vol.80, p.109923-109923, Article 109923
Main Authors: Wang, Jiwen, Ni, Xiaojian, Shen, Sheng, Zhang, Dexiang, Ni, Xiaoling, Suo, Tao, Lu, Pinxiang, Fan, Kun, Liu, Han, Liu, Houbao
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Cell Movement - drug effects
Cyclin-Dependent Kinase Inhibitor p27 - metabolism
Cytoplasm - metabolism
E2F1 Transcription Factor - genetics
E2F1 Transcription Factor - metabolism
Gallbladder carcinoma
Gallbladder Neoplasms - metabolism
Gallbladder Neoplasms - pathology
Glucose - pharmacology
Glucose deficiency
Humans
Metastasis
p27
Phosphorylation - drug effects
RNA Interference
RNA, Small Interfering - metabolism
Stathmin - antagonists & inhibitors
Stathmin - genetics
Stathmin - metabolism
Stathmin1
Transcription, Genetic - drug effects
Tumor Suppressor Proteins - antagonists & inhibitors
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Up-Regulation
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Summary:Gallbladder carcinoma (GBC) is a considerable challenge because of its high metastatic potential. The tumor microenvironment is characterized by nutrient starvation, which promotes tumor metastasis. Stathmin1, an important microtubuleregulating protein, is overexpressed and promotes metastasis in GBC. It remains unclear how the harsh tumor microenvironment regulates stathmin1 expression to affect GBC metastasis. We employed glucose deficiency to mimic nutrient starvation and found that glucose deficiency upregulated stathmin1 transcription. However, glucose deficiency also promoted p27 degradation. There was a significant negative correlation between stathmin1 and p27 protein levels under glucose deficiency. Further study revealed that, under glucose deficiency, human kinase interacting with stathmin (hKIS) induced phosphorylation at Ser10 of p27 and its translocation to the cytoplasm for degradation, which upregulated the transcription factor E2F1 to promote stathmin1 transcription. hKIS knockdown significantly inhibited p27 cytoplasmic translocation and its consequent degradation. Stathmin1 knockdown significantly inhibited GBC cell migration and invasion in vitro. Our study revealed the role of the hKIS/p27/E2F1 axis in upregulating stathmin1 transcription to promote GBC cell migration and invasion under glucose deficiency conditions •We model the nutrition starvation conditions with glucose deficiency;•We found increased levels of stathmin1 of GBC in nutrition starvation condition;•Glucose deficiency induced phosphorylation of p27Kip1 at Ser10 and consequently degradation;•Phosphorylation of p27 at Ser10 promoted GBC migration and invasion;•hKIS/p27/E2F1 axis regulated stathmin1 expression and GBC cell migration and invasion under glucose deficiency conditions.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2021.109923