The mediator complex in genomic and non-genomic signaling in cancer

Abstract

Mediator is a conserved, multi-subunit macromolecular machine divided structurally into head, middle, and tail modules, along with a transiently associating kinase module. Mediator functions as an integrator of transcriptional regulatory activity by interacting with DNA-bound transcription factors and with RNA polymerase II (Pol II) to both activate and repress gene expression. Mediator has been shown to affect multiple steps in transcription, including chromatin looping between enhancers and promoters, pre-initiation complex formation, transcriptional elongation, and mRNA splicing. Individual Mediator subunits participate in regulation of gene expression by the estrogen and androgen receptors and are altered in a number of endocrine cancers, including breast and prostate cancer. In addition to its role in genomic signaling, MED12 has been implicated in non-genomic signaling by interacting with and activating TGF-beta receptor 2 in the cytoplasm. Recent structural studies have revealed extensive inter-domain interactions and complex architecture of the Mediator-Pol II complex, suggesting that Mediator is capable of reorganizing its conformation and composition to fit cellular needs. We propose that alterations in Mediator subunit expression that occur in various cancers could impact the organization and function of Mediator, resulting in changes in gene expression that promote malignancy. A better understanding of the role of Mediator in cancer could reveal new approaches to the diagnosis and treatment of Mediator-dependent endocrine cancers, especially in settings of therapy resistance.

Development of a novel lipid metabolism-based risk score model in hepatocellular carcinoma patients

“…MED10 and MED22 are both subunits of the Mediator complex, an evolutionary conserved multiprotein complex consisting of approximately 30 subunits. The Mediator complex functions as a transcriptional coactivator in eukaryotes [ 37 , 38 ], regulating the expression of most RNA polymerase II-transcribed genes [ 39 ]. Understanding the function of the Mediator complex in cancer is critical, as it may guide the development of novel anti-cancer therapies [ 40 ].…”

Identification of lipid metabolism-associated genes as prognostic biomarkers based on the immune microenvironment in hepatocellular carcinoma

“…MED7 and MED22 are subunits of the mediator complex (MED). MED proteins play a key role in eukaryotic transcription ( Malik and Roeder, 2010 ) by regulating the ability of transcription factors to transfer information to the polymerase II-transcription machinery ( Weber and Garabedian, 2018 ). With respect to other tumors, MED7 underexpression was correlated with an increased risk of gastrointestinal stroma ( Koschubs et al, 2009 ), while in breast cancer, especially ER + luminal subtypes, MED7 was positively correlated with improved prognosis ( Joseph et al, 2018 ).…”

MED10 Drives the Oncogenicity and Refractory Phenotype of Bladder Urothelial Carcinoma Through the Upregulation of hsa-miR-590

“…This is consistent with accruing evidence of the tumor-promoting roles of components of the multi-protein Mediator complex, including reports that Mediator subunit CDK19 is specifically expressed in prostate cancer, with upregulated expression being associated with disease progression, as observed in patients with metastatic and castration-resistant disease ( 28 ). More so, several reports indicate that other subunits of the Mediator complex, which are actively involved in regulating estrogen and androgen receptor gene expression, are altered in some endocrine malignancies, such as prostate and breast cancer ( 19 , 20 , 29 ). We also show, for the first time to the best of our knowledge, that MED10 expression is positively correlated with disease progression, immune suppression, and therapy failure.…”