A coregulatory role for the mediator complex in prostate cancer cell proliferation and gene expression

被引:60
作者
Vijayvargia, Ravi
May, Michael S.
Fondell, Joseph D.
机构
[1] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Physiol & Biophys, Piscataway, NJ 08854 USA
[2] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol, New Brunswick, NJ 08903 USA
关键词
D O I
10.1158/0008-5472.CAN-06-3039
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 All. 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 MEDI/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.
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收藏
页码:4034 / 4041
页数:8
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