Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types

Abstract

The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking.We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.

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

“…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.…”

“…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).…”

Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer

“…By integrating and transmitting diverse regulative signals, for example, from transcription factors to RNA Polymerase II, Mediator complex function may impact almost all cellular processes . Numerous studies reported aberrant activities of distinct Mediator subunits contributing to the pathogenesis of diverse disorders including cancer . Several genes encoding Mediator subunits are affected by chromosomal aberrations or gene mutations in cancer cells and certain subunits affect cancer‐related pathways by specific molecular interference .…”

“…2 Numerous studies reported aberrant activities of distinct Mediator subunits contributing to the pathogenesis of diverse disorders including cancer. [3][4][5] Several genes encoding Mediator subunits are affected by chromosomal aberrations 6,7 or gene mutations [8][9][10] in cancer cells and certain subunits affect cancerrelated pathways by specific molecular interference. 11,12 Therefore, particular subunits have been implied to define certain molecular cancer subtypes and serve as therapeutic targets.…”

Mediator Complex Subunit MED1 Protein Expression Is Decreased during Bladder Cancer Progression

“…Immunohistochemical staining was conducted on TMAs using the Ventana Benchmark automated staining system (Ventana Medical System, Tuscon, AZ, USA) as described previously (7, 9, 18, 19). In brief, slides were incubated at room temperature with the primary antibody: anti-TRAP220/MED1 rabbit polyclonal (dilution 1:500, ab64965, lot number: GR54026, Abcam).…”