Abstract
In the United States, prostate cancer is the most common cancer affecting men and the second leading cause of male cancer-related deaths. Current treatments for prostate cancer revolve around androgen ablation therapy. This type of therapy results in a 60-80% initial response rate. In most patients, this therapy only offers relief for a brief period of time. Most commonly, patients develop a more aggressive form of prostate cancer that is immune to androgen ablation therapy and is therefore termed androgen-independent prostate cancer (AIPC). This accelerated form of prostate cancer correlates with increased activity or expression of the androgen receptor (AR), akt1, and c-jun. Previous work in our laboratory has shown that this increased activity of the androgen receptor can be attributed to hyperacetylation at a conserved sequence motif, in turn promoting cellular growth and proliferation. It was this presence of AR hyperacetylation and the direct correlation that exists between age and prostate cancer onset and severity that led us to investigate the potential role of Sirtuin histone deacetylases, namely Sirt1, as potential therapeutic targets against prostate cancer. The Sirtuin family consists of a group of NAD+-dependent histone deacetylases that are conserved from archaeobacteria to eukaryotes. SIRT1 is the human homolog of the yeast Silent Information Regulator 2 (Sir2) gene associated with longevity. SIRT1 deacetylates multiple substrates including histones, transcription factors, as well as nuclear receptors and their co-activators such as the AR and p300. This study\#8217;s purpose is to define the functional role of Sirt1 in androgen signaling and prostate cellular growth and development in vivo. Herein, homozygous deletion of the Sirt1 gene in mice results in altered size and morphology of androgen-responsive tissues and decreased levels of serum FSH, LH, and testosterone. Microarray analysis demonstrates that Sirt1 regulates a distinct subset of androgen-responsive genes involved in vital biological pathways such as cell proliferation, metabolism, organ development, immune response and apoptosis. Furthermore, miRNA chip analysis shows that Sirt1 regulates DHT-responsive miRNA that possess putative binding sites within crucial developmental genes such as the homeobox gene, Nkx3.1. Collectively, these studies provide potential mechanisms by which Sirt1 regulates androgen signaling, in turn effecting DHT-dependent cellular proliferation and growth as well as the expression of specific homeobox genes essential for normal prostate development. These findings have direct implications for the treatment of prostate cancer by proposing a mechanism by which Sirt1 can revert prostatic hyperplasia/dysplasia through the manipulation of androgen signaling.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4126.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
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