oru.sePublikationer
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
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.
Pathology, University Medical Center Schleswig-Holstein, Campus Lübeck, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany.
Pathology, University Medical Center Schleswig-Holstein, Campus Lübeck, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany.
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.
Show others and affiliations
2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 7, 1829-1840 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for Cancer Research Inc. , 2017. Vol. 23, no 7, 1829-1840 p.
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:oru:diva-57061DOI: 10.1158/1078-0432.CCR-16-0094ISI: 000398262700022PubMedID: 27678455ScopusID: 2-s2.0-85016948550OAI: oai:DiVA.org:oru-57061DiVA: diva2:1089021
Note

Funding Agencies:

Rudolf Becker-Foundation

Wilhelm Sander Foundation  2011.077.2

German Research Foundation  DFG PE1179/9-1  PE1179/11-1

Ferdinand Eisenberger-Fellowship of the German Society of Urology (DGU)  SYI1/FE-13

Medical Faculty of the University of Bonn  2014-11-06

"Mildred-Scheel medical doctoral programme" grant of the German Cancer Aid 

Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2017-04-18Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Carlsson, JessicaAndrén, OveSvensson, Maria A.
By organisation
School of Medical SciencesOrebro University Hospital
In the same journal
Clinical Cancer Research
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 12 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf