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- Braegelmann, Johannes, et al.
(författare)
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Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
- 2017
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research Inc.. - 1078-0432 .- 1557-3265. ; 23:7, s. 1829-1840
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Tidskriftsartikel (refereegranskat)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 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.
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| 2. |
- Shaikhibrahim, Zaki, et al.
(författare)
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MED12 overexpression is a frequent event in castration-resistant prostate cancer
- 2014
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Ingår i: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 21:4, s. 663-675
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Tidskriftsartikel (refereegranskat)abstract
- In a recent effort to unravel the molecular basis of prostate cancer (PCa), Barbieri and colleagues using whole-exome sequencing identified a novel recurrently mutated gene, MED12, in 5.4% of primary PCa. MED12, encoding a subunit of the Mediator complex, is a transducer of Wnt/beta-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGF beta)-receptor signaling. Therefore, these studies prompted us to investigate the relevance of MED12 in PCa. Expression of MED12, SMAD3 phosphorylation, and proliferation markers was assessed by immunohistochemistry on tissue microarrays from 633 patients. siRNA-mediated knockdown of MED12 was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGF beta 3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPCMET) and 21% (19/90) of local-recurrent CRPC (CRPCLOC) in comparison with frequencies of less than 11% in androgen-sensitive PCa, and no overexpression in benign prostatic tissues. MED12 expression was significantly correlated with high proliferative activity in PCa tissues, whereas knockdown of MED12 decreased proliferation, reduced G1-to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGF beta signaling activation associates with MED12 nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, MED12 knockdown reduced the expression of the TGF beta target gene vimentin. Our findings show that MED12 nuclear overexpression is a frequent event in CRPC in comparison with androgen-sensitive PCa and is directly implicated in TGF beta signaling.
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