The Role of the Transcriptional Coactivator p300 in Prostate Cancer Progression

摘要

Although the factors contributing to the progression of prostate cancer (PC) remain incompletely understood, androgens have long been recognized to play a central role in this process. Upon entering PC cells, androgens bind to a cognate nuclear receptor, the androgen receptor (AR). The activated AR translocates to the nucleus, binds as a dimer to androgen response elements (AREs) in the promoter of target genes, where it recruits the coactivator proteins necessary for the formation of a productive transcriptional complex, an event crucial for PC cell viability. For many decades, the androgen dependency of PCs has been exploited therapeutically by androgen ablation strategies. Although initially successful, these forms of therapy almost inevitably fail eventually, and an androgen depletion independent (ADI) disease emerges, for which currently no cure is available. Studies from our laboratory and others demonstrate mat despite low circulating levels of functional androgens, the AR is critical for the proliferation and survival of ADI PC cells. Recent data indicate that alterations in the expression and/or activity of AR coactivator proteins occur during PC progression that can foster ADI activation of the AR. Here, we have investigated the role of the coactivator p300 in AR transcriptional activity and progression of PC.