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Shaikhibrahim, Zaki; Offermann, Anne; Braun, Martin; Menon, Roopika; Syring, Isabella; Nowak, Michael; Halbach, Rebecca; Vogel, Wenzel; Ruiz, Christian; Zellweger, Tobias; Rentsch, Cyrill A; Svensson, Maria; Andren, Ove; Bubendorf, Lukas; Biskup, Saskia; Duensing, Stefan; Kirfel, Jutta; Perner, Sven

MED12 overexpression is a frequent event in castration-resistant prostate cancer

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  • Media type: E-Article
  • Title: MED12 overexpression is a frequent event in castration-resistant prostate cancer
  • Contributor: Shaikhibrahim, Zaki; Offermann, Anne; Braun, Martin; Menon, Roopika; Syring, Isabella; Nowak, Michael; Halbach, Rebecca; Vogel, Wenzel; Ruiz, Christian; Zellweger, Tobias; Rentsch, Cyrill A; Svensson, Maria; Andren, Ove; Bubendorf, Lukas; Biskup, Saskia; Duensing, Stefan; Kirfel, Jutta; Perner, Sven
  • imprint: Bioscientifica, 2014
  • Published in: Endocrine-Related Cancer
  • Language: Not determined
  • DOI: 10.1530/erc-14-0171
  • ISSN: 1351-0088; 1479-6821
  • Origination:
  • Footnote:
  • Description: <jats:p>In a recent effort to unravel the molecular basis of prostate cancer (PCa), Barbieri and colleagues using whole-exome sequencing identified a novel recurrently mutated gene, <jats:italic>MED12</jats:italic>, in 5.4% of primary PCa. <jats:italic>MED12</jats:italic>, encoding a subunit of the Mediator complex, is a transducer of Wnt/β-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGFβ)-receptor signaling. Therefore, these studies prompted us to investigate the relevance of MED12 in PCa. Expression of MED12, SMAD3 phosphorylation, and proliferation markers was assessed by immunohistochemistry on tissue microarrays from 633 patients. siRNA-mediated knockdown of <jats:italic>MED12</jats:italic> was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGFβ3. We found nuclear overexpression of <jats:italic>MED12</jats:italic> in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPC<jats:sup>MET</jats:sup>) and 21% (19/90) of local-recurrent CRPC (CRPC<jats:sup>LOC</jats:sup>) in comparison with frequencies of less than 11% in androgen-sensitive PCa, and no overexpression in benign prostatic tissues. MED12 expression was significantly correlated with high proliferative activity in PCa tissues, whereas knockdown of <jats:italic>MED12</jats:italic> decreased proliferation, reduced G1- to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGFβ signaling activation associates with <jats:italic>MED12</jats:italic> nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, <jats:italic>MED12</jats:italic> knockdown reduced the expression of the TGFβ target gene vimentin. Our findings show that <jats:italic>MED12</jats:italic> nuclear overexpression is a frequent event in CRPC in comparison with androgen-sensitive PCa and is directly implicated in TGFβ signaling.</jats:p>
  • Access State: Open Access