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Pan-Cancer Analysis...
Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
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- Braegelmann, Johannes (author)
- 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
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- Kluemper, Niklas (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Offermann, Anne (author)
- 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 (author)
- 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
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- Böhm, Diana (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Deng, Mario (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Queisser, Angela (author)
- 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
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- Sanders, Christine (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Syring, Isabella (author)
- 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
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- Merseburger, Axel S. (author)
- Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany
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- Vogel, Wenzel (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Sievers, Elisabeth (author)
- Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany
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- Vlasic, Ignacija (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Carlsson, Jessica, 1984- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Urology, Örebro University Hospital, Örebro, Sweden
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- Andrén, Ove, 1963- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Urology, Örebro University Hospital, Örebro, Sweden
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- Brossart, Peter (author)
- Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany; Department of Hematology, Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany
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- Duensing, Stefan (author)
- Molecular Uro-oncology, Department of Urology, University of Heidelberg, Heidelberg, Germany
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- Svensson, Maria A., 1980- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Research and Education, Örebro University Hospital, Örebro, Sweden
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- Shaikhibrahim, Zaki (author)
- Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany
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- Kirfel, Jutta (author)
- Institute of Pathology, University Hospital of Bonn, Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany
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- Perner, Sven (author)
- 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
- English.
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In: Clinical Cancer Research. - : American Association for Cancer Research Inc.. - 1078-0432 .- 1557-3265. ; 23:7, s. 1829-1840
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Onkologi
- Oncology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Braegelmann, Joh ...
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Kluemper, Niklas
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Offermann, Anne
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Von Maessenhause ...
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Böhm, Diana
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Deng, Mario
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show more...
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Queisser, Angela
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Sanders, Christi ...
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Syring, Isabella
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Merseburger, Axe ...
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Vogel, Wenzel
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Sievers, Elisabe ...
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Vlasic, Ignacija
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Carlsson, Jessic ...
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Andrén, Ove, 196 ...
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Brossart, Peter
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Duensing, Stefan
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Svensson, Maria ...
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Shaikhibrahim, Z ...
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Kirfel, Jutta
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Perner, Sven
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Clinical Cancer ...
- By the university
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Örebro University