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MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer
Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn Germany .
Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn Germany .
Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn Germany .
Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn Germany .
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2014 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 1, p. 19-26Article in journal (Refereed) Published
Abstract [en]

The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-beta 3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPCMET) and 70% of local-recurrent CRPC (CRPCLOC), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-beta signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-beta-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model.

Place, publisher, year, edition, pages
Hoboken: Wiley-Blackwell, 2014. Vol. 135, no 1, p. 19-26
Keywords [en]
castration-resistant, prostate cancer, MED15, TGF-beta
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:oru:diva-35108DOI: 10.1002/ijc.28647ISI: 000334353500003OAI: oai:DiVA.org:oru-35108DiVA, id: diva2:718748
Note

Funding Agencies:

Emmy Noether-Program

Wilhelm Sander-Foundation

German Research Foundation [Deutsche Forschungsgemeinschaft (DFG)]

Rudolf Becker-Foundation

Medical Faculty of the University of Bonn (BONFOR)

Available from: 2014-05-22 Created: 2014-05-22 Last updated: 2018-06-07Bibliographically approved

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Andrén, Ove

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Svensson, MariaAndrén, Ove
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Örebro University HospitalSchool of Health and Medical Sciences, Örebro University, Sweden
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