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MED12 overexpression is a frequent event in castration-resistant prostate cancer
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
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2014 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 4, p. 663-675Article in journal (Refereed) Published
Abstract [en]

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, MED12, in 5.4% of primary PCa. MED12, encoding a subunit of the Mediator complex, is a transducer of Wnt/beta-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGF beta)-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 MED12 was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGF beta 3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPCMET) and 21% (19/90) of local-recurrent CRPC (CRPCLOC) 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 MED12 decreased proliferation, reduced G1-to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGF beta signaling activation associates with MED12 nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, MED12 knockdown reduced the expression of the TGF beta target gene vimentin. Our findings show that MED12 nuclear overexpression is a frequent event in CRPC in comparison with androgen-sensitive PCa and is directly implicated in TGF beta signaling.

Place, publisher, year, edition, pages
Bioscientifica, 2014. Vol. 21, no 4, p. 663-675
Keywords [en]
MED12, overexpression, prostate cancer, castration-resistant
National Category
Cancer and Oncology Endocrinology and Diabetes
Research subject
Oncology
Identifiers
URN: urn:nbn:se:oru:diva-39814DOI: 10.1530/ERC-14-0171ISI: 000344788200032PubMedID: 24938407Scopus ID: 2-s2.0-84905993098OAI: oai:DiVA.org:oru-39814DiVA, id: diva2:772146
Note

Funding Agencies:

German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)

Emmy-Noether-Program PE1179/2-1

Rudolf-Becker-Foundation

Wilhelm-Sander-Foundation 2011.077.1

(BONFOR) of the Medical Faculty of the University of Bonn

Ferdinand Eisenberger Fellowship of the German Society of Urology (DGU)

Medical Faculty Heidelberg of the University of Heidelberg

Available from: 2014-12-16 Created: 2014-12-16 Last updated: 2020-12-01Bibliographically approved

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Andrén, Ove

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