De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells

// Yan-hua Ren 1,2,* , Ke-jia Liu 1,* , Ming Wang 1 , Ya-nan Yu 3 , Kai Yang 1 , Qin Chen 1 , Bin Yu 1 , Wei Wang 4 , Qi-wei Li 4 , Jian Wang 4 , Zhao-yuan Hou 1 , Jing-yuan Fang 3 , Edward T. Yeh 5 , Jie Yang 1 , Jing Yi 1 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 Correspondence: 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 Abstract 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.