SUMO-Specific Cysteine Protease 1 Promotes Epithelial Mesenchymal Transition of Prostate Cancer Cells via Regulating SMAD4 deSUMOylation.
SUMO-Specific Cysteine Protease 1 Promotes Epithelial Mesenchymal Transition of Prostate Cancer Cells via Regulating SMAD4 deSUMOylation.
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SUMO 特异性半胱氨酸蛋白酶 1 通过调节 SMAD4 去 SUMO 化促进前列腺癌细胞的上皮间质转化
DOI：
10.3390/ijms18040808
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发表时间：
2017-04-12
影响因子：
5.6
通讯作者：
Wang L
中科院分区：
文献类型：
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作者：
Zhang X;Wang H;Wang H;Xiao F;Seth P;Xu W;Jia Q;Wu C;Yang Y;Wang L
在晚期前列腺癌中，小泛素样修饰物(SUMO)特异性半胱氨酸蛋白酶1(SENP1)表达上调。然而，SENP1在调节转化生长因子-β/SMADS信号去苏氨化中的作用尚不清楚。在本研究中，我们开发了一种慢病毒载体PLKO.1-shSENP1，在具有高转移特性的前列腺癌细胞(PC3M)中沉默SENP1。同样，我们还创建了腺病毒载体Ad5/F11p-SENP1，以在低转移潜能的前列腺癌细胞(LNCaP)中过表达SENP1。我们发现，沉默SENP1促进了细胞的凋亡，抑制了PC3M细胞的增殖和迁移。此外，SENP1沉默在蛋白水平上上调了Smad4的表达，上调了E-钙粘蛋白的表达，下调了Vimentin的表达，从而抑制了上皮间质转化(EMT)。此外，Smad4干扰取消了SENP1介导的E-cadherin的上调，表明SENP1通过Smad4调节E-cadherin的表达。SENP1在LNCaP细胞中的过表达降低了Smad4蛋白的表达，并通过降低E-钙粘蛋白和升高Vimentin促进了EMT。此外，Smad4和E-cadherin的下调被阻断，提示SENP1可能通过Smad4的去SUMO作用来降低Smad4的水平，从而调节E-cadherin的表达。总之，SENP1去SUMO化Smad4通过上调前列腺癌细胞中的E-钙粘附素来促进EMT。因此，SENP1是治疗晚期前列腺癌的潜在靶点。
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.