This proposal aims to determine a new mechanism regulating androgen receptor (AR) function in prostate cancer cellular growth. Prostate cancer progression correlates with increased activity/expression of AR, Akt1, c-jun and cyclin D1 and reduced histone acetylation. We showed the AR is acetylated at a conserved motif, that this AR acetylation site promotes cellular growth by regulating recruitment of HDAC/NCoR/Smad complexes to the promoters of a subset of cell-cycle regulatory genes. We showed that 1. AR acetylation and phosphorylation are linked, 2. SirT1 expression and function are regulated by dihydrotestosterone (DHT) and metabolism 3. AR is repressed by the NAD-dependent histone deacetylases (SirT1), and 4. AR acetylation site is a target of Akt/c-jun/cyclin D1/Sirt1. The proposed studies will determine in vivo the functional significance of Akt/c-jun/cyclin D1/Sirt1 in AR function.
Aim 1. Determine in vivo significance of AR regulation by Akt1 and cyclin D1. AR expression and function are enhanced by Akt and inhibited by cyclin D1 in cultured tumor cell lines. Akt1-/- and cyclin D1-/- prostate epithelial cells will be examined in 2D and 3D culture and in the prostate in vivo.
Aim 2. Determine in vivo significance of AR regulation by c-jun and SirT1. c-jun enhances and SirT1 represses AR function in cultured prostate cancer cells. The role of c-jun and SirT1 in regulating AR function in vivo is unknown due to the embryonic or perinatal lethality of genetic deletion. We will determine the role of c- jun and Sirt1 in AR signaling using c-junfl/fl and SirT1fl/fl mice Aim 3. Determine functional significance of Sirt1 in prostate cellular growth in vivo. The AR acetylation site functions as a growth switch of the AR in prostate cancer cells in culture and in nude mice. Sirt1 inhibits AR-mediated prostate cellular growth. We will determine the functional significance of Sirt1 in prostate growth in vivo using SirT1fl/fl mice and Probasin CRE mice. Prostate cancer is the most frequently diagnosed cancer in men in the United States and the second leading cause of male cancer deaths. Prostate cancer unresponsive to therapy emerges in patients. These three integrated Aims will determine the role of an Akt/c-jun/cyclin D1/SirT1 pathway in AR function in vivo and thereby identify key new therapeutic options.
The mechanisms governing androgen ablation therapy resistance of prostate cancer involves hyperactivation of the AR. A subset of key genes correlate with prostate cancer outcome and/or have been shown to regulate AR activity in prostate cancer cells in tissue culture (Akt1, c-Jun, cyclin D1, Sirt1), however, the role of these key genes in regulating AR function in vivo is not known, therefore, we have generated genetic deletion models in the mouse. As our studies show acetylation of the AR governs the growth properties of the AR in human prostate cancer cells and the AR acetylation site is a key target through which these genes (Akt1, c-Jun, cyclin D1, Sirt1) regulate the AR, we have developed new prostate cancer cell lines to conduct mechanistic studies of the regulation of AR acetylation by these target genes.
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