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YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin.

Authors
  • Khan, Mohammad Imran
  • Adhami, Vaqar Mustafa
  • Lall, Rahul Kumar
  • Sechi, Mario
  • Joshi, Dinesh C
  • Haidar, Omar M
  • Syed, Deeba Nadeem
  • Siddiqui, Imtiaz Ahmad
  • Chiu, Shing-Yan
  • Mukhtar, Hasan
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
May 15, 2014
Volume
5
Issue
9
Pages
2462–2474
Identifiers
PMID: 24770864
Source
Medline
License
Unknown

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.

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