Characterization of the NAD-Dependent Human Histone Deacetylases Gene Sirtuin 1 and Its Implications on Aging and the Development of Malignant Disease.

A dysregulation of the tightly controlled equilibrium of acetylation and deacetylation plays a causative role in the generation as well as in the suppression of cancer. Histone acetylation modifiers are therefore gaining increasing attention as potential targets in the treatment of cancer. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which belongs to the silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the human Sirt1 genomic sequence and identified a number of SIRT1 protein interaction partners, which will be important for the further understanding its physiological role. The Sirt1 gene spans a region of 33,660 bp and is located on chromosome 10q21.3. The protein is localized in the nucleus, and interacts with and deacetylates a growing number of proteins, such as p53, the Forkhead transcription factor FOXO3A, PML, BCL6, TAF_I68, HES1, and CTIP2. SIRT1 has been shown to be essential for embryonic development, muscle differentiation and is an important mediator of organismal longevity through a number of different mechanisms such as the induction of cell cycle arrest, resistance to oxidative stress and the inhibition of apoptosis.

Some histone deacetylase genes have been shown to be rearranged in the context of chromosomal translocations in human acute leukemias and solid tumors, where fusions of regulatory and coding regions of a variety of transcription factor genes result in completely new gene products, which may interfere with regulatory cascades that control cell growth and differentiation. On the other hand, some histone acetylation modifying enzymes have been located within chromosomal regions that are particularly prone to chromosomal breaks. In these cases gains and losses of chromosomal material may affect the availability of functionally active HATs and HDACs, which in turn disturbs the tightly controlled equilibrium of histone acetylation. A deletion of Sirt1 would therefore most probably shift the steady state toward acetylation at the level of specific genes targeted by SIRT1 and either upregulate or downregulate transcriptional events. Such dysregulation might represent a critical event in the multistep pathway leading to full cellular transformation and the development of malignancy.