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Clin Cancer Res. 2017 Apr 1;23(7):1829-1840. doi: 10.1158/1078-0432.CCR-16-0094. Epub 2016 Sep 27.

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

Author information

1
Section for Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany.
2
Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
3
Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
4
Department of Hematology, Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany.
5
Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany.
6
Clinic for Urology and Pediatric Urology, University Hospital of Bonn, Bonn, Germany.
7
Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany.
8
Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
9
Molecular Uro-oncology, Department of Urology, University of Heidelberg, Heidelberg, Germany.
10
Department of Research and Education, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
11
Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany. Sven.Perner@uksh.de.

Abstract

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 cancer was marked 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 CDK8 were present in metastases. In vitro, inhibition of CDK19 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. Clin Cancer Res; 23(7); 1829-40. ©2016 AACR.

PMID:
27678455
DOI:
10.1158/1078-0432.CCR-16-0094
[Indexed for MEDLINE]
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