Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

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Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

Braegelmann, Johannes (författare): Section for Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany; Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany; Department of Hematology, Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany

Kluemper, Niklas (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Offermann, Anne (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

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Von Maessenhausen, Anne (författare): Section for Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany; Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany

Böhm, Diana (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Deng, Mario (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Queisser, Angela (författare): Section for Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany; Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany

Sanders, Christine (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Syring, Isabella (författare): Section for Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany; Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany; Clinic for Urology and Pediatric Urology, University Hospital of Bonn, Bonn, Germany

Merseburger, Axel S. (författare): Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany

Vogel, Wenzel (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Sievers, Elisabeth (författare): Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany

Vlasic, Ignacija (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Carlsson, Jessica, 1984- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Urology, Örebro University Hospital, Örebro, Sweden

Andrén, Ove, 1963- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Urology, Örebro University Hospital, Örebro, Sweden

Brossart, Peter (författare): Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany; Department of Hematology, Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany

Duensing, Stefan (författare): Molecular Uro-oncology, Department of Urology, University of Heidelberg, Heidelberg, Germany

Svensson, Maria A., 1980- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Research and Education, Örebro University Hospital, Örebro, Sweden

Shaikhibrahim, Zaki (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

Kirfel, Jutta (författare): Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany

Perner, Sven (författare): Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

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(creator_code:org_t)

American Association for Cancer Research Inc. 2017
2017
Engelska.
Ingår i: Clinical Cancer Research. - : American Association for Cancer Research Inc.. - 1078-0432 .- 1557-3265. ; 23:7, s. 1829-1840

Relaterad länk:: https://urn.kb.se/re...; visa fler...; https://doi.org/10.1...; visa färre...

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Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches.Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq.Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancerwasmarked by high expression of CDK19. In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8were present inmetastases. In vitro, inhibition ofCDK19 and CDK8 by knockdown or treatment with a selective CDK8/ CDK19 inhibitor significantly decreased migration and invasion.Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer.

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Cancer och onkol ...

Artiklar i publikationen: Clinical Cancer ...

Av lärosätet: Örebro universitet

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Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

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