Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer.
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 ofCDK19andCDK8was 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 ofCDK19In primary prostate cancer,CDK19was 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 identifiedCDK19andCDK8to 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.
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.
Johannes
J
Brägelmann
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.
Niklas
N
Klümper
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.
Anne
A
Offermann
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.
Anne
A
von Mässenhausen
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.
Diana
D
Böhm
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.
Mario
M
Deng
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.
Angela
A
Queisser
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.
Christine
C
Sanders
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.
Isabella
I
Syring
Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany.
Axel S
AS
Merseburger
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.
Wenzel
W
Vogel
Institute of Pathology, University Hospital of Bonn, Bonn, Germany.|Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
Elisabeth
E
Sievers
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.
Ignacija
I
Vlasic
Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Jessica
J
Carlsson
Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Ove
O
Andrén
Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.|Department of Hematology, Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany.
Peter
P
Brossart
Molecular Uro-oncology, Department of Urology, University of Heidelberg, Heidelberg, Germany.
Stefan
S
Duensing
Department of Research and Education, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Maria A
MA
Svensson
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.
David
D
Adler
Institute of Pathology, University Hospital of Bonn, Bonn, Germany.|Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
Jutta
J
Kirfel
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.
Sven
S
Perner
D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics
D056892:Mediator Complex; C584437:CDK19 protein, human; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases