The Contrasting Role of the Mediator Subunit MED30 in the Progression of Bladder Cancer

Syring, Isabella; Weiten, Richard; Müller, Timo; Schmidt, Doris; Steiner, Susanne; Kristiansen, Glen; Müller, Stefan; Ellinger, Jörg

doi:10.21873/anticanres.12127

Cited by 3 publications

(3 citation statements)

References 27 publications

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“…Loss of MED30 resulted in dramatically decreased proliferation in embryonic cardiomyocytes, and increased apoptosis in adult cardiomyocytes. Similar effects on cell cycle and cell viability have been observed in Med30 knockdown cancer cell lines [45,46]. MED30 is located within the Mediator core.…”

Section: Discussionsupporting

confidence: 69%

Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network

et al. 2021

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Dysregulation of cardiac transcription programs has been identified in patients and families with heart failure, as well as those with morphological and functional forms of congenital heart defects. Mediator is a multi-subunit complex that plays a central role in transcription initiation by integrating regulatory signals from gene-specific transcriptional activators to RNA polymerase II (Pol II). Recently, Mediator subunit 30 (MED30), a metazoan specific Mediator subunit, has been associated with Langer-Giedion syndrome (LGS) Type II and Cornelia de Lange syndrome-4 (CDLS4), characterized by several abnormalities including congenital heart defects. A point mutation in MED30 has been identified in mouse and is associated with mitochondrial cardiomyopathy. Very recent structural analyses of Mediator revealed that MED30 localizes to the proximal Tail, anchoring Head and Tail modules, thus potentially influencing stability of the Mediator core. However, in vivo cellular and physiological roles of MED30 in maintaining Mediator core integrity remain to be tested. Here, we report that deletion of MED30 in embryonic or adult cardiomyocytes caused rapid development of cardiac defects and lethality. Importantly, cardiomyocyte specific ablation of MED30 destabilized Mediator core subunits, while the kinase module was preserved, demonstrating an essential role of MED30 in stability of the overall Mediator complex. RNAseq analyses of constitutive cardiomyocyte specific Med30 knockout (cKO) embryonic hearts and inducible cardiomyocyte specific Med30 knockout (icKO) adult cardiomyocytes further revealed critical transcription networks in cardiomyocytes controlled by Mediator. Taken together, our results demonstrated that MED30 is essential for Mediator stability and transcriptional networks in both developing and adult cardiomyocytes. Our results affirm the key role of proximal Tail modular subunits in maintaining core Mediator stability in vivo.

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Section: Discussionsupporting

confidence: 69%

Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network

et al. 2021

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“…Previous studies have described the expression and role of mediator complex subunits in carcinogenesis, progression, and invasion. However, MED30 has only been examined in gastric, renal, and breast cancers [ 32 , 33 , 34 ]. In gastric cancer, overexpression of MED30 increases proliferation, migration, and invasion.…”

Section: Discussionmentioning

confidence: 99%

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation

et al. 2022

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Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC‐recurrence‐related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low‐ and high‐risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.

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“…For examples, genetic variations in SLC14A1 have been linked to the development of bladder cancer 44,45 and its upregulation has been suggested as a potential target for clinical intervention 46,47 . In addition, a negative regulatory role of MED30 has been recently revealed in that its overexpression can suppress the progression of bladder cancer 48 .…”

Section: Number Of Observationsmentioning

confidence: 99%

HDMAC: A Web-Based Interactive Program for High-Dimensional Analysis of Molecular Alterations in Cancer

Chang

Sung

Hsiao

et al. 2020

Sci Rep

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Recent advances in high-throughput genomic technologies have nurtured a growing demand for statistical tools to facilitate identification of molecular changes as potential prognostic biomarkers or drugable targets for personalized precision medicine. in this study, we developed a web-based interactive and user-friendly platform for high-dimensional analysis of molecular alterations in cancer (HDMAc) (https://ripsung26.shinyapps.io/rshiny/). on HDMAc, several penalized regression models that are suitable for high-dimensional data analysis, Ridge, Lasso and adaptive Lasso, are offered, with Cox regression for survival and logistic regression for binary outcomes. Choice of a first-step screening is provided to address the multiple-comparison issue that often arises with large-volume genomic data. Hazard ratio or estimated coefficient is provided with each selected gene so that a multivariate regression model may be built based on the genes selected. cross validation is provided as the method to estimate the prediction power of each regression model. in addition, R codes are also provided to facilitate download of whole sets of molecular variables from tcGA. in this study, illustration of the use of HDMAc was made through a set of data on gene mutations and a set on mRnA expression from ovarian cancer patients and a set on mRnA expression from bladder cancer patient. from the analysis of each set of data, a list of candidate genes was obtained that might be associated with mutations or abnormal expression of genes in ovarian and bladder cancers. HDMAC offers a solution for rigorous and validation analysis of high-dimensional genomic data. Recent advances in high-throughput technologies such as microarrays and next generation sequencing have enabled researchers to identify molecular changes that are associated with cancers in a systematic way 1,2. Such efforts have attracted much attention as the molecular changes may represent potential prognostic biomarkers or drugable targets for personalized precision medicine. Meanwhile, several multiple-data platforms, e.g., the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), have also become available to researchers when identifying genome-wide molecular changes of individual cancers 3,4. With these updated tools and consortiums, there emerges a growing demand for statistical tools to facilitate identification of molecular changes. There are several web tools available for researchers to analyze genomic data. For example, cBioPortal provides simultaneous display of RNA expression, mutations, copy number alterations and protein expression with multiple choices of plots for visualization 5,6. HPA and Protein Expression Atlas are specialized in protein expression.

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The Contrasting Role of the Mediator Subunit MED30 in the Progression of Bladder Cancer

Abstract: MED30 appears to be integrated in the progression of the urothelial tumour in the bladder.

Cited by 3 publications

References 27 publications

Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network

Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation

HDMAC: A Web-Based Interactive Program for High-Dimensional Analysis of Molecular Alterations in Cancer

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