Abstract
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.
Highlights
Prostate cancer (PCa) is the leading cause of cancer related deaths among American men
The major findings of this study are: (i) Forced overexpression of Y-box binding protein-1 (YB-1) in presence of EGF induces persistent epithelial to mesenchymal transition (EMT) in non-tumorigenic prostate cells, (ii) YB-1 phosphorylation is strongly induced by EGF in prostate cells, (iii) YB-1 expression is inversely correlated with E-cadherin in human PCa samples, (iv) fisetin interacts within the cold shock domain (CSD) domain of YB-1 resulting in reduction in YB-1 phosphorylation at ser102 by reducing its interaction with activating Akt kinase and (v) fisetin inhibits EMT in both xenograft and in well-established in vitro TGF-β model suggesting its potential as an EMT inhibitor in PCa
It may be possible that these cells were not supported by extracellular growth signaling/factors like EGF, IGF, bFGF etc. known to phosphorylate YB-1, which seems to be important for its oncogenic function and EMT inducing properties
Summary
Prostate cancer (PCa) is the leading cause of cancer related deaths among American men. When detected early the five year survival rate is close to 100% detection at advanced metastatic stages severely declines the overall survival [1]. These statistics suggest that high mortality in PCa patients is due to metastasis. Epithelial cells rely on a very fine tuned and highly regulated program known as epithelial to mesenchymal transition (EMT) that converts them into a mesenchymal state. Cancer cells use this program to metastasize and colonize at distant sites [2]. Among them Y-box–binding protein-1 (YB1) is a recently identified protein known to induce EMT in different cancers [7]
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