YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin.
YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin.
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DOI：
10.18632/oncotarget.1790
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Mukhtar H
中科院分区：
文献类型：
--
作者：
Khan MI;Adhami VM;Lall RK;Sechi M;Joshi DC;Haidar OM;Syed DN;Siddiqui IA;Chiu SY;Mukhtar H
上皮向间充质转化(EMT)在前列腺癌(PCa)转移中起重要作用。转录/翻译调节的Y盒结合蛋白-1(YB-1)被认为与肿瘤转移有关。我们观察到YB-1在人前列腺癌组织阵列中的表达随着肿瘤分级的增加而增加，并且与E-钙粘附素呈负相关。强迫YB-1表达诱导了与上皮标志物下调相关的间质形态。YB-1的沉默逆转了PCa细胞间充质的特征，减少了细胞的增殖、迁移和侵袭。YB-1通过Akt介导的冷休克结构域(CSD)内Ser102的磷酸化被直接激活。接下来，我们发现非瑟素是YB-1激活的抑制因子。计算对接和分子动力学表明，非瑟素与β1-β4链的残基结合，阻碍了Akt与YB-1的相互作用。计算的自由结合能范围为−11.9845~−9.6273千卡/摩尔。等离子体表面共振研究表明，非瑟素与YB-1以约35μM的亲和力结合，既有缓慢的结合，也有解离。非瑟素在体内外均能抑制EGF诱导的YB-1磷酸化和EMT标志物的表达。总之，我们的数据表明，YB-1诱导了前列腺癌的EMT，并发现非瑟素是其激活的抑制物。
Epithelial-to-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis. The transcription/translation regulatory Y-box binding protein-1 (YB-1) is known to be associated with cancer metastasis. We observed that YB-1 expression increased with tumor grade and showed an inverse relationship with E-cadherin in a human PCa tissue array. Forced YB-1 expression induced a mesenchymal morphology that was associated with down regulation of epithelial markers. Silencing of YB-1 reversed mesenchymal features and decreased cell proliferation, migration and invasion in PCa cells. YB-1 is activated directly via Akt mediated phosphorylation at Ser102 within the cold shock domain (CSD). We next identified fisetin as an inhibitor of YB-1 activation. Computational docking and molecular dynamics suggested that fisetin binds on the residues from β1 - β4 strands of CSD, hindering Akt's interaction with YB-1. Calculated free binding energy ranged from −11.9845 to −9.6273 kcal/mol. Plasmon Surface Resonance studies showed that fisetin binds to YB-1 with an affinity of approximately 35 μM, with both slow association and dissociation. Fisetin also inhibited EGF induced YB-1 phosphorylation and markers of EMT both in vitro and in vivo. Collectively our data suggest that YB-1 induces EMT in PCa and identify fisetin as an inhibitor of its activation.
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