The role of the Mediator complex subunits MED12 and MED15 in the development of androgen-dependent prostate cancer into androgen-independent castration resistant prostate cancer

• Applicant: Professor Dr. Sven Perner
• Subject Area: Pathology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268940839

• Final Report Year: 2020

Final Report Abstract

In the first part of this project, we have achieved main aims of this grant focusing on the role of MED15 in PCa. Our results highlight that MED15 is involved in the development of CRPC and connected to cancer-driven pathways including PI3K activation. Inhibiting MED15 under androgen deprived conditions reflecting circumstances under androgen deprivation therapy in patients induced apoptosis of cells suggesting to further investigating MED15 inhibition as therapeutic target for CRPC. Subsequently, we explored the involvement of the Mediator subunit CDK19 in PCa instead of MED12 as initially intended. Hereby, we found that CDK19 is up-regulated in advanced, metastatic PCa and predicts disease recurrence suggesting CDK19 as prognostic biomarker for risk stratification. Results of following in vitro analyses mainly contribute to a better understanding of its molecular functions in PCa. We observed that CDK19 has major impact on both gene transcription as well as post-translational protein modification through phosphorylation of multiple cancer-related substrates. Furthermore, CDK19 inhibition by diverse recently developed small molecule inhibitors resulted in significant anti-tumor effects such as impaired migration and invasion. First results of follow-up projects show that CDK19 inhibition might sensitize CRPC cells to androgen-blockade suggesting that the combined treatment with established androgen deprivation and simultaneous CDK19 inhibition might be a promising therapeutic option for patients. Collectively, these projects contribute to better understand the molecular involvement of the Mediator complex in human cancers. Several Mediator subunits have been linked to cancer-related pathways and specific cancer entities highlighting its crucial involvement in cancer initiation, progression and the development of therapy resistance. CDK8, the gene paralog of CDK19, is a known colon cancer oncogene and contributes to diverse pro-tumorigenic cellular processes. Therefore, multiple small molecule inhibitors targeting CDK8 and CDK19 have been recently developed. Results of our tissue and function in vitro experiments strongly suggest testing these inhibitors for the treatment of patients suffering from metastatic and/or castration-resistant PCa. Results of this study provided the basis for subsequent follow-up projects which are currently ongoing.

Publications

• Clinical and molecular implications of MED15 in head and neck squamous cell carcinoma. Am J Pathol. 2015 Apr;185(4):1114-22
  Shaikhibrahim Z, Offermann A, Halbach R, Vogel W, Braun M, Kristiansen G, Bootz F, Wenzel J, Mikut R, Lengerke C, Reischl M, Schröck A, Perner S
  
• Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types. Oncotarget. 2016 Apr 26;7(17):23043-55
  Syring I, Klümper N, Offermann A, Braun M, Deng M, Boehm D, Queisser A, von Mässenhausen A, Brägelmann J, Vogel W, Schmidt D, Majores M, Schindler A, Kristiansen G, Müller SC, Ellinger J, Shaikhibrahim Z, Perner S
  
• IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2. Am J Pathol. 2016 Apr;186(4):974-84
  Merz C, von Mässenhausen A, Queisser A, Vogel W, Andrén O, Kirfel J, Duensing S, Perner S, Nowak M
  
• MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling. Oncotarget. 2017 Jan 31;8(5):7964-7976
  Offermann A, Vlasic I, Syring I, Vogel W, Ruiz C, Zellweger T, Rentsch CA, Hagedorn S, Behrends J, Nowak M, Merseburger A, Bubendorf L, Kirfel J, Duensing S, Shaikhibrahim Z, Perner S
  
• Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer. Clin Cancer Res. 2017 Apr 1;23(7):1829-1840
  Brägelmann J, Klümper N, Offermann A, von Mässenhausen A, Böhm D, Deng M, Queisser A, Sanders C, Syring I, Merseburger AS, Vogel W, Sievers E, Vlasic I, Carlsson J, Andrén O, Brossart P, Duensing S, Svensson MA, Shaikhibrahim Z, Kirfel J, Perner S
  
• TRIM24 as an independent prognostic biomarker for prostate cancer. Urol Oncol. 2019 Sep;37(9):576.e1-576.e10
  Offermann A, Roth D, Hupe MC, Hohensteiner S, Becker F, Joerg V, Carlsson J, Kuempers C, Ribbat-Idel J, Tharun L, Sailer V, Kirfel J, Svensson M, Andren O, Lubczyk V, Kuefer R, Merseburger AS, Perner S
  
• Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer. Int J Cancer. 2020 Jan 15;146(2):577-588
  Becker F, Joerg V, Hupe MC, Roth D, Krupar R, Lubczyk V, Kuefer R, Sailer V, Duensing S, Kirfel J, Merseburger AS, Brägelmann J, Perner S, Offermann A