Involvement of Mediator complex in malignancy

Schiano, Concetta; Casamassimi, Amelia; Rienzo, Monica; Nigris, Filomena de; Sommese, Linda; Napoli, Claudio

doi:10.1016/j.bbcan.2013.12.001

Cited by 76 publications

(96 citation statements)

References 134 publications

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“…Recently, an increasing number of Mediator complex subunits have been identified as relevant components in a range of human diseases including different cancer entities (3,4,7). To foster the knowledge of Mediator complex biology in human cancers and to evaluate its complex and potentially entity-specific subunit composition, we performed a pan-cancer analysis of Mediator complex transcriptome profiles.…”

Section: Discussionmentioning

confidence: 99%

“…The kinase module including subunits cyclin-dependent kinase 8 (CDK8), MED12, MED13, and cyclin C (CCNC) can reversibly associate with the core structure, which leads to considerable changes of MED confirmation and functional activity (3). In addition, in vertebrates, the subunits CDK19, MED12L, and MED13L have been shown to take part in formation of the kinase module in a mutually exclusive manner with their paralogous counterparts CDK8, MED12, and MED13, respectively, indicating a high flexibility in MED composition and its quaternary structure (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several subunits have been implicated in a growing number of human diseases including developmental disorders (3,6) and cancer (4,7). 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).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…It has been shown that med12 gene is essential for early development in mouse and is involved in the transcriptional regulation of many signaling pathways (Philibert and Madan, 2007, Rocha et al, 2010). MED12 has been shown to be implicated in a number of neurological disorders (Xu et al, 2011, Philibert and Madan, 2007, Sandhu et al, 2003, Graham and Schwartz, 2013, Risheg et al, 2007, Schwartz et al, 2007, Ding et al, 2008) as well as human cancers (Schiano et al, 2014, Turunen et al, 2014, Huang et al, Shalem et al, 2014, Wang et al, 2015). Particularly, MED12 was linked to drug resistance in multiple cancer types including breast, colon, lung cancers and melanoma (Wang et al, 2015, Shalem et al, 2014, Huang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex

et al. 2018

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SUMMARY Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC domain-containing proteins in mediating enhancer activation remain poorly understood. Here we report that recruitment of the JmjC domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 was found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer, coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.

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“…In addition, how a single complex can be involved in ensuring tight transcriptional regulation of hundreds or thousands of genes through different specific interactions with TFs is largely unknown. The importance of the complex is highlighted by the fact that many Mediator subunits are involved in human diseases like neurodevelopmental pathologies or cancers (Kaufmann et al 2010;Hashimoto et al 2011;Spaeth et al 2011;Schiano et al 2014).…”

mentioning

confidence: 99%

Functional interplay between Mediator and TFIIB in preinitiation complex assembly in relation to promoter architecture

et al. 2016

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Mediator is a large coregulator complex conserved from yeast to humans and involved in many human diseases, including cancers. Together with general transcription factors, it stimulates preinitiation complex (PIC) formation and activates RNA polymerase II (Pol II) transcription. In this study, we analyzed how Mediator acts in PIC assembly using in vivo, in vitro, and in silico approaches. We revealed an essential function of the Mediator middle module exerted through its Med10 subunit, implicating a key interaction between Mediator and TFIIB. We showed that this Mediator-TFIIB link has a global role on PIC assembly genome-wide. Moreover, the amplitude of Mediator's effect on PIC formation is gene-dependent and is related to the promoter architecture in terms of TATA elements, nucleosome occupancy, and dynamics. This study thus provides mechanistic insights into the coordinated function of Mediator and TFIIB in PIC assembly in different chromatin contexts.

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Involvement of Mediator complex in malignancy

Cited by 76 publications

References 134 publications

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

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

JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex

Functional interplay between Mediator and TFIIB in preinitiation complex assembly in relation to promoter architecture

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