YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin
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Mohammad Imran Khan1, Vaqar Mustafa Adhami1, Rahul Kumar Lall1, Mario Sechi3, Dinesh C. Joshi2, Omar M. Haidar1, Deeba Nadeem Syed1, Imtiaz Ahmad Siddiqui1, Shing-Yan Chiu2, Hasan Mukhtar1
1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI
2 Department of Neurophysiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI
3 Department of Chemistry and Pharmacy, University of Sassari, Italy
Hasan Mukhtar, email:
Keywords: Y-box potein-1, Fisetin, EMT, Prostate cancer, invasion, migration
Received: January 22, 2014 Accepted: February 18, 2014 Published: February 19, 2014
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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