<i>MED15</i>, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration‐resistant prostate cancer

Shaikhibrahim, Zaki; Menon, Roopika; Braun, Martin; Offermann, Anne; Queisser, Angela; Boehm, Diana; Vogel, Wenzel; Rüenauver, Kerstin; Ruiz, Christian; Zellweger, Tobias; Svensson, Maria A.; Andrén, Ove; Kristiansen, Glen; Wernert, Nicolas; Bubendorf, Lukas; Kirfel, Jutta; Biskup, Saskia

doi:10.1002/ijc.28647

Cited by 30 publications

(39 citation statements)

References 13 publications

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“…Recently, we have found similar expression patterns in PCa tissues and functional results in cell lines for the Mediator tail subunit MED15 (Shaikhibrahim et al 2013). The interplay between different subunits of the Mediator complex provides the basis for the function of the Mediator as a hub between signaling pathways and the transcription of specific genes.…”

Section: Discussionmentioning

confidence: 60%

“…The response of metastatic PCa cell lines to TGFb depends on the cellular microenvironment. In a recent study, we observed increased proliferation of the PCa cell line PC3 in response to exogenous TGFb3 when cells were grown in the presence of all growth factors (Shaikhibrahim et al 2013). Other studies showed that TGFb treatment had no effect upon proliferation in PC3 cells when cells were plated in serum-free medium (Vo et al 2012).…”

Section: Introductionmentioning

confidence: 81%

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MED12 overexpression is a frequent event in castration-resistant prostate cancer

Shaikhibrahim¹,

Offermann²,

Braun³

et al. 2014

Endocrine-Related Cancer

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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/b-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGFb)-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 TGFb3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPC MET ) and 21% (19/90) of local-recurrent CRPC (CRPC LOC ) 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. TGFb 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

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 81%

MED12 overexpression is a frequent event in castration-resistant prostate cancer

Shaikhibrahim¹,

Offermann²,

Braun³

et al. 2014

Endocrine-Related Cancer

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“…Most evidence has been gathered for the kinase module subunit CDK8, which has been linked to colon and pancreatic cancer (8,9) and was also investigated as a potential target in cancer therapy (10,11). Other subunits have also been reported in neoplastic conditions such as MED12 in uterine leiomyomas, fibroepithelial breast tumors, and prostate cancer (12)(13)(14), MED15 in prostate cancer and head and neck cancer (15,16), and cyclin C in acute lymphoblastic leukemia (17). In addition, some subunits have been linked to altered hormone receptor signaling such as MED1 in breast cancer and prostate cancer (18,19).…”

Section: Introductionmentioning

confidence: 99%

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

Brägelmann

Klümper²,

Offermann³

et al. 2016

Clinical Cancer Research

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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 ¼ 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 ¼ 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.

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“…21 We recently reported the implication of MED15 in castration-resistant prostate cancer and its direct link to transforming growth factor (TGF)-b signaling in this disease. 22 Notably, TGF-b signaling is involved in HNSCC, 23 and a large study reported alterations in SMADdependent TGF-b signaling at high frequency and revealed that patients with active SMAD signaling exhibited worse survival rates. 24 Moreover, abnormalities in SMAD-interacting proteins have been described to contribute to dysregulated TGF-b signaling.…”

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confidence: 99%

“…24 Moreover, abnormalities in SMAD-interacting proteins have been described to contribute to dysregulated TGF-b signaling. 21,22,25 Therefore, we aimed to investigate whether MED15 is implicated in HNSCC and thus further contribute to the understanding of the molecular basis of this disease.…”

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confidence: 99%

Clinical and Molecular Implications of MED15 in Head and Neck Squamous Cell Carcinoma

Shaikhibrahim¹,

Offermann²,

Halbach³

et al. 2015

The American Journal of Pathology

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Head and neck squamous cell carcinoma (HNSCC) progression depends on various dysregulated pathways. Regulation of diverse pathways is mediated by the mediator complex. The mediator subunit MED15 is essential for transforming growth factor (TGF)-β signaling and involved in breast and prostate cancers. We investigated the implication of MED15 in HNSCC. IHC for MED15 was performed on 324 tissue samples, and TGF-β assessed the use of Ki-67 and pSMAD3 as markers. MED15 knockdown followed by proliferation and migration assays, as well as TGF-β1 treatment followed by MED15 analysis, was also performed. MED15 was overexpressed in 35% of primary tumors, 30% of lymph node metastases, and 70% of recurrences in contrast to no or low expression in benign tumors. MED15 overexpression in primary tumors from patients who developed recurrences was associated with higher mortality rates and occurred at highest frequency in oral cavity or oropharyngeal tumors. Furthermore, MED15 expression correlated between primary tumors and corresponding lymph node metastases. MED15 correlated with proliferation in tissues, and MED15 knockdown reduced proliferation and migration. We observed an association between MED15 and TGF-β activity in tissues because TGF-β activation led to increased MED15 expression and reduced pSMAD3 on MED15 knockdown. Taken together, our results implicate MED15 in HNSCC and hint that MED15 overexpression is a clonal event during HNSCC progression. MED15 may serve as a prognostic marker for recurrence and as a therapeutic target.

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MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration‐resistant prostate cancer

Cited by 30 publications

References 13 publications

MED12 overexpression is a frequent event in castration-resistant prostate cancer

MED12 overexpression is a frequent event in castration-resistant prostate cancer

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

Clinical and Molecular Implications of MED15 in Head and Neck Squamous Cell Carcinoma

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