SUMO-Specific Cysteine Protease 1 Promotes Epithelial Mesenchymal Transition of Prostate Cancer Cells via Regulating SMAD4 deSUMOylation.

Abstract

In advanced prostate cancer, small ubiquitin-like modifier (SUMO)-specific cysteine protease 1 (SENP1) is up-regulated. However, the role of SENP1 in regulating deSUMOylation of TGF-β/SMADs signaling is unknown. In this study, we developed a lentiviral vector, PLKO.1-shSENP1, to silence SENP1 in prostate cancer cells with high metastatic characteristics (PC3M). Likewise, we also created an adenovirus vector, Ad5/F11p-SENP1 to over-express SENP1 in prostate cancer cells with low metastatic potential (LNCaP). We showed that silencing of SENP1 promoted cellular apoptosis, and inhibited proliferation and migration of PC3M cells. Moreover, SENP1 silencing increased the SMAD4 expression at protein level, up-regulated E-cadherin and down-regulated Vimentin expression, indicating the inhibition of epithelial mesenchymal transition (EMT). Furthermore, SMAD4 interference abolished SENP1-mediated up-regulation of E-cadherin, suggesting that SENP1 regulated E-cadherin expression via SMAD4. SENP1 over-expression in LNCaP cells reduced SMAD4 protein, and promoted EMT via decreasing E-cadherin and increasing Vimentin. Moreover, down-regulation of SMAD4 and E-cadherin were blocked, after transfection with two SUMOylation sites mutated SMAD4, suggesting that SENP1 might reduce SMAD4 levels to regulate E-cadherin expression via deSUMOylation of SMAD4. In conclusion, SENP1 deSUMOylated SMAD4 to promote EMT via up-regulating E-cadherin in prostate cancer cells. Therefore, SENP1 is a potential target for treatment of advanced prostate cancer.

• Authors: Xiaoyan Zhang, Hao Wang, Hua Wang, Fengjun Xiao, Prem Seth, Weidong Xu, Qinghua Jia, Chutse Wu, Yuefeng Yang, Lisheng Wang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 4 (Apr 12 2017) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 28417919 (Publication Type: Journal Article)

Chemical References

• Androgens
• RNA, Small Interfering
• Smad4 Protein
• Transforming Growth Factor beta
• Endopeptidases
• SENP1 protein, human
• Cysteine Endopeptidases

Topics

• Androgens
• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cysteine Endopeptidases
• Endopeptidases (metabolism)
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Male
• Prostatic Neoplasms (genetics, metabolism, pathology)
• RNA, Small Interfering (genetics)
• Signal Transduction
• Smad4 Protein (metabolism)
• Sumoylation
• Transforming Growth Factor beta (metabolism)