Role of p53 in the anti-proliferative effects of Sirt1 inhibition in prostate cancer cells.

Prostate cancer (PCa), next only to skin cancer, is the most commonly occurring malignancy in men in the US. Aging is recognized as a major risk factor for this neoplasm as a man's chance for developing this disease significantly increases with increasing age. Because aging is inevitable, Americans are living longer, and the existing treatments have not been able to manage this neoplasm, novel mechanism-based approaches are needed. We have recently shown that Sirt1, a sirtuin class III histone deacetylases (HDACs) originally linked to aging and longevity in yeast, was overexpressed in human PCa cells and PCa tissues obtained from patients. We also found that chemical inhibition and/or genetic knockdown of Sirt1 caused a FoxO1-mediated inhibition in the growth and viability of human PCa cells. Since p53 is a target for deacetylation by Sirt1, we wanted to determine the involvement of p53 in Sirt1 inhibition mediated responses in PCa. To achieve our objective, we utilized a pair of isogenic PCa cell lines viz. PC3 and PC3-p53, which differ only in p53 status. Our data demonstrated that Sirt1 inhibition caused a decrease in cell growth, cell viability and the colony formation ability of both cell lines. Further, Sirt1 inhibition resulted in an increase in FoxO1 acetylation and subsequent transcriptional activation in both cell types regardless of p53 status. However, an interesting observation of our study was that Sirt1 inhibition resulted in an increase in senescence in PC3-p53 cells whereas it resulted in an increase in apoptosis in PC3 cells. The results of this study compliment our previous study and suggest that Sirt1 inhibition may have different downstream targets in cells with active p53 versus cells where p53 is inactive.