De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells
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Yan-hua Ren1,2,*, Ke-jia Liu1,*, Ming Wang1 , Ya-nan Yu3, Kai Yang1, Qin Chen1, Bin Yu1, Wei Wang4, Qi-wei Li4, Jian Wang4, Zhao-yuan Hou1, Jing-yuan Fang3, Edward T. Yeh5, Jie Yang1, Jing Yi1
1 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Institute of Neuroscience, Wenzhou Medical University, School of Medicine, Zhejiang, China
3 Department of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
4 Department of Biliary- Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
5 Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
* These authors contribute equally to the work
Jing Yi, email:
Jie Yang, email:
Keywords: epithelial-mesenchymal transition (EMT); reactive oxygen species (ROS); SENP3; SUMO2/3; FOXC2; gastric cancer
Received: May 25, 2014 Accepted: July 07, 2014 Published: July 09, 2014
The impact of cellular oxidative stress in promoting the epithelial-mesenchymal transition (EMT) has been noticed. Our previous study shows that SENP3, a redox-sensitive SUMO2/3-specific protease, accumulates in a variety of cancers, but whether SENP3 and SUMOylation involve in the regulation of EMT is unclear. The present study uncovers a novel role of SENP3 in promoting the EMT process in gastric cancer via regulating an EMT-inducing transcription factor, forkhead box C2 (FOXC2). We demonstrate that the expression of mesenchymal marker genes and cell migration ability are enhanced in SENP3-overexpressing gastric cancer cells and attenuated in SENP3-knockdown cells. A nude mouse model and a set of patient’s specimens suggest the correlation between SENP3 and gastric cancer metastasis. Biochemical assays identify FOXC2 as a substrate of SENP3. Meanwhile N-cadherin is verified as a target gene of FOXC2, which is transcriptionally activated by a SUMO-less FOXC2. Additionally, reactive oxygen species-induced de-SUMOylation of FOXC2 can be blocked by silencing endogenous SENP3. In conclusion, SENP3, which is increased in gastric cancer cells, potentiates the transcriptional activity of FOXC2 through de-SUMOylation, in favor of the induction of specific mesenchymal gene expression in gastric cancer metastasis.
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