Abstract
Androgen receptor (AR) signaling pathways are important for the survival and proliferation of prostate cancer cells. Because AR activity is facilitated by distinct coregulatory factors and complexes, it is conceivable that some of these proteins might also play a role in promoting prostate oncogenesis. The multisubunit Mediator complex is an important coactivator for a broad range of regulatory transcriptional factors including AR, yet its role in prostate cancer is unclear. Here, we used RNA interference to knock down the expression of two integral Mediator components, MED1/TRAP220 and MED17, in prostate cancer cells. MED1/TRAP220 plays a particularly important role in androgen signaling in that it serves as a direct binding target for AR. We found that the knockdown of either subunit markedly decreases transcription from transiently transfected androgen-responsive reporter genes, as well as inhibits androgen-dependent expression of endogenous AR target genes. We show for the first time that loss of either MED1/TRAP220 or MED17 in prostate cancer cells significantly decreases both androgen-dependent and -independent cellular proliferation, inhibits cell cycle progression, and increases apoptosis. Furthermore, we show that MED1/TRAP220 is overexpressed in both AR-positive and -negative prostate cancer cells lines, as well as in 50% (10 of 20) of the clinically localized human prostate cancers we examined, thus suggesting that MED1/TRAP220 hyperactivity may have implications in prostate oncogenesis. In sum, our data suggest that Mediator plays an important coregulatory role in prostate cancer cell proliferation and survival, and therefore, may represent a new target for therapeutic intervention.
Highlights
Androgen receptor (AR) signaling pathways are important for the growth and survival of both normal and early stage neoplastic prostate cells [1]
We show that MED1/TRAP220 is overexpressed in both AR-positive and -negative prostate cancer cells lines, as well as in clinically localized prostate cancers, suggesting that MED1/TRAP220 hyperactivity might promote prostate oncogenesis
MED1/TRAP220 and MED17 are both important for androgen-dependent gene expression in prostate cancer cells
Summary
Androgen receptor (AR) signaling pathways are important for the growth and survival of both normal and early stage neoplastic prostate cells [1]. Because AR activity in prostate cells is critically dependent on interactions with an assortment of coregulatory proteins and complexes [4], it has been proposed that overexpression or hyperactivation of distinct AR cofactors may facilitate important oncogenic events in both prostate cancer initiation and progression to the androgen-independent disease [3, 4]. In addition to NR coactivation, MED1/TRAP220 may play a pivotal role in cellular growth and cell cycle regulation. Consistent with this notion, MED1/TRAP220 can serve as a binding target for other transactivators involved in cell growth and development including the GATA family proteins [22], p53 [23], BRCA-1 [24], and GABPa [25]
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