MED29, a component of the mediator complex, possesses both oncogenic and tumor suppressive characteristics in pancreatic cancer

Abstract

Mediator complex subunit 29 (MED29) is part of a large multiprotein coactivator complex that mediates regulatory signals from gene-specific activators to general transcription machinery in RNA polymerase II mediated transcription. We previously found that MED29 is amplified and overexpressed in pancreatic cancer and that MED29 silencing leads to decreased cell survival in PANC-1 pancreatic cancer cells with high MED29 expression. Here we further demonstrate decreased migration, invasion and colony formation in PANC-1 cells after MED29 silencing. Unexpectedly, lentiviral-based overexpression of MED29 led to decreased proliferation of NIH/3T3 cells as well as MIAPaCa-2 pancreatic cancer cells with low endogenous expression. More importantly, subcutaneous inoculation of the MED29-transduced pancreatic cancer cells into immuno-compromised mice resulted in dramatic tumor suppression. The mock-control mice developed large tumors, whereas the animals with MED29-xenografts showed both decreased tumor incidence and a major reduction in tumor size. Gene expression analysis in the MED29-transduced pancreatic cancer cells revealed differential expression of genes involved in control of cell cycle and cell division. The observed gene expression changes are expected to modulate the cell cycle in a way that leads to reduced cell growth, explaining the in vivo tumor suppressive phenotype. Taken together, these data implicate MED29 as an important regulator of key cellular functions in pancreatic cancer with both oncogenic and tumor suppressive characteristics. Such a dualistic role appears to be more common than previously thought and is likely to depend on the genetic background of the cancer cells and their surrounding environment.

Mediator links transcription and DNA repair by facilitating Rad2/XPG recruitment

“…Recently, mutations in the Med17 Mediator subunit have been associated with infantile cerebral atrophy (Kaufmann et al 2010), and a mutation in the Med23 subunit cosegregated with intellectual disability (Hashimoto et al 2011). Since oncogenesis results from gene disregulation, it is not unexpected that Mediator is involved in several cancers (Zhang et al 2005;Vijayvargia et al 2007;Firestein et al 2008;Gade et al 2009;Li et al 2010;Kuuselo et al 2011). Mediator has at least 25 subunits organized into four modules: head, middle, tail, and Cdk8 kinase modules.…”

The Prognostic Significance and Tumor-promoting Roles of MED30 in Pancreatic Cancer

“…MED23 was associated with lung cancers with hyperactive Ras signaling, and its expression levels was correlated with poor prognosis [17]. Many studies have suggested mediator complex subunits as oncogenic functional components on carcinogenic progress [18,19], although mechanisms related to these phenotypes are unknown. Since the mediator complex has been described as the end point of the cell signaling pathway, different transcription factors bind speci c mediator subunits to activate transcriptional regulation.…”

Erratum

“…Nonetheless, scarce literature addressed the individual role of Mediator subunit in cellular migration. Recently, Kuuselo et al (2011) described that suppression of MED29, a Mediator component, decreased migration and invasion in PANC‐1 pancreatic cancer cells. Previously we reported that MED28 modulated EGF‐induced migration by phosphatidylinositol 3‐kinase/Akt/MMP9 signaling pathway in breast cancer cells (Lee et al, 2011).…”