It is estimated that a man's chance of developing prostate cancer (PCa) increases with age; 1 in 2,500 by age 45; 1 in 120 by age 55; and 1 in 9 by age 75; suggesting that aging is a risk factor for PCa. Therefore, it is important to identify the genetic determinant(s) that connect PCa and aging. Sirtuins or Sir2 (silent information regulator 2)-related enzymes, which are a family of nicotinamide adenine dinucleotide-dependent class III histone deacetylases, have been shown to deacetylate lysine residues on various proteins. The most well studied member of sirtuin family, Sirt1 has been shown to be involved in a number of cellular processes including gene silencing, DNA repair, recombination and aging. Studies have shown that several forms of cancer have elevated levels of Sirt1 and are dependent on Sirt1 for proliferation and survival. It is suggested that a loss of tumor-suppressor genes that regulate Sirt1 may lead to an overexpression of Sirt1, thereby imparting a proliferative advantage to cancer cells. Recent studies have also suggested that Sirt1 plays an important role in the regulation of cell fate and promotes cell survival by modulating apoptosis and/or cellularsenescence, the two important tumor suppressor mechanisms which have evolved in organisms. We have earlier shown that Sirt1 is significantly overexpressed in human PCa tissues compared to adjacent normal or benign prostate tissues. In this study, we attempted to determine the functional significance of Sirt1 in human PCa cells. Employing a variety of human PCa cells (DU145, LNCaP, 22Rν1, and PC3) and normal prostate epithelial cells (PrEC), we first determined the endogenous levels of Sirt1. Our data demonstrated that Sirt1 was significantly overexpressed in DU145, LNCaP, 22Rν1, and PC3 cells compared to normal PrEC cells, at the protein, mRNA and enzyme activity levels. Next, we determined the effect of Sirt1 knockdown on PCa cells employing two distinct approaches viz. i) chemical knockdown of Sirt1 enzyme by nicotinamide, and ii) genetic knockdown of Sirt1 gene via short hairpin RNA (shRNA)-mediated RNA interference. Our data demonstrated that nicotinamide treatment of PCa cells resulted in a significant decrease in Sirt1 enzyme activity as well as the growth and viability of human PCa cells. Similarly, shRNA-mediated knockdown of Sirt1 resulted in significant inhibition in Sirt1 protein and activity as well as growth and viability of human PCa cells. Taken together, our data suggested that i) Sirt1 overexpression could be a contributing factor in human PCa development, and ii) Sirt1 could serve as a potential target towards developing novel strategies for the management of this age-related malignancy. However, future studies in appropriate in vitro and in vivo systems are needed to delineate the mechanism(s) by which Sirt1 imparts a growth advantage to PCa cells.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA