Dataset Information

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

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.

SUBMITTER: Ren YH

PROVIDER: S-EPMC4196186 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Ren Yan-hua YH Liu Ke-jia KJ Wang Ming M Yu Ya-nan YN Yang Kai K Chen Qin Q Yu Bin B Wang Wei W Li Qi-wei QW Wang Jian J Hou Zhao-yuan ZY Fang Jing-yuan JY Yeh Edward T ET Yang Jie J Yi Jing J

Oncotarget 20140801 16

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 demonstrat ...[more]

PMID: 25216525

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Project description:Background:Tumor metastasis is an important factor in treatment failure for advanced gastric cancer. Family with sequence similarity 3 member C (FAM3C) is known to play a critical role in inducing epithelial-mesenchymal transition in several cancer types, while its role in gastric cancer is unidentified. The aim of this study was to investigate the role of FAM3C in gastric cancer and provide new information on the receptor tyrosine-kinase pathway and cytokine-based therapies. Methods:FAM3C expression was tested in human gastric cancer tissue and adjacent normal mucosa, and the prognostic effect of FAM3C was analyzed in data from the Cancer Genome Atlas (TCGA). The role of FAM3C in gastric cancer proliferation and metastasis was investigated in vitro and in vivo. Western blot analysis and immunofluorescence were used to detect the underlying mechanisms. Results:FAM3C expression was increased in gastric cancer tissue and showed cytoplasmic distribution. Gastric cancer patients with FAM3C overexpression had significantly worse prognoses based on TCGA data. In the gastric cancer cell lines MKN45 and AGS, knockdown of FAM3C dramatically attenuated cell migration, but had almost no influence on proliferation, while exogenous FAM3C promoted cell migration in a cell line with low FAM3C expression. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of TCGA data showed that FAM3C was mainly associated with genes involved in focal adhesion, extracellular matrix-receptor interactions and the PI3K-Akt signaling pathway. Knockdown of FAM3C in gastric cancer cell lines significantly suppressed epithelial-mesenchymal transition, as demonstrated by increased expression of E-cadherin and decreased expression of Snail and Slug. Furthermore, knockdown of FAM3C strongly suppressed activation of the PI3K-Akt signaling pathway. Finally, we confirmed that FAM3C knockdown significantly decreased metastatic lesions in vivo. Conclusion:Our study demonstrated that FAM3C can promote gastric cancer metastasis both in vitro and in vivo. FAM3C should be taken into consideration for gastric cancer treatments involving inhibition of the ligands and downstream pathways of receptor tyrosine kinases.

Dataset Information

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

Publications

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

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