期刊
ONCOTARGET
卷 5, 期 16, 页码 7093-7104出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2197
关键词
epithelial-mesenchymal transition (EMT); reactive oxygen species (ROS); SENP3; SUMO2/3; FOXC2; gastric cancer
资金
- National Ministry of Science and Technology of China (973 project) [2013CB910900]
- National Natural Science Foundation of China [31230037]
- Shanghai Municipal Science and Technology Commission [11JC1406900, 11DZ2260200]
- Zhejiang Provincial Natural Science Foundation of China [LQ14H160018]
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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