The Mediator complex is a multi-protein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Since 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.
We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n=8568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer (PCa) specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced PCa (n=622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA mediated gene knock-down and inhibitor treatment in PCa cell lines with functional assays and gene expression analysis by RNAseq.
Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type specific Mediator complex compositions. Only PCa was marked by high expression of CDK19. In primary PCa 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 knock-down or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion.
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 PCa progression, highlighting their potential as novel therapeutic targets in advanced PCa.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Sep 27 [Epub ahead of print]
Johannes Brägelmann, Niklas Klümper, Anne Offermann, Anne von Mässenhausen, Diana Böhm, Mario Deng, Angela Queisser, Christine Sanders, Isabella Syring, Axel S Merseburger, Wenzel Vogel, Elisabeth Sievers, Ignacija Vlasic, Jessica Carlsson, Ove Andrén, Peter Brossart, Stefan Duensing, Maria A Svensson, Zaki Shaikhibrahim, Jutta Kirfel, Sven Perner
Section for Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn., Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences., Department of Prostate Cancer Research, Institute of Pathology, University Hospital Bonn., Institute of Pathology, Department of prostate cancer research, University Hospital Bonn., Dept. of Prostate Cancer Research, University Hospital of Bonn., Institute of Pathology, University Hospital of Bonn., Urology; campus Lubeck, University Hospital Schleswig-Holstein Ratzeburger., Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences., Med., University of Bonn., Department of Urology, University Hospital of Örebro., Urology, Örebro University Hospital., Department of Internal Medicine III, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB)., Molecular Urooncology, University of Heidelberg., University Hospital of Örebro, Department of Urology., Institute of Pathology, Bonn Medical School., Institute of Pathology, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences .