23411

SIRT1

SIR2|SIR2L1|hSIR2;sirtuin 1;SIRT1;sirtuin 1

NAD-dependent deacetylase sirtuin-1|NAD-dependent protein deacetylase sirtuin-1|SIR2-like protein 1|SIR2alpha|regulatory protein SIR2 homolog 1|sir2-like 1|sirtuin type 1

10q21.3

protein-coding

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+)-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.

In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity, and genome stability. Here we mutated the Sirt1 gene, a homolog of yeast Sir2, in mice to study its function. We show that a majority of SIRT1 null embryos die between E9.5 and E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrate that Sirt1(+/-);p53(+/-) mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis. Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity.

The protein deacetylase SIRT1 has been implicated in a variety of cellular functions, including development, cellular stress responses, and metabolism. Increasing evidence suggests that similar to its counterpart, Sir2, in yeast, Caenorhabditis elegans, and Drosophila melanogaster, SIRT1 may function to regulate life span in mammals. However, SIRT1s role in cancer is unclear. During our investigation of SIRT1, we found that c-Myc binds to the SIRT1 promoter and induces SIRT1 expression. However, SIRT1 interacts with and deacetylates c-Myc, resulting in decreased c-Myc stability. As a consequence, c-Mycs transformational capability is compromised in the presence of SIRT1. Overall, our experiments identify a c-Myc-SIRT1 feedback loop in the regulation of c-Myc activity and cellular transformation, supporting/suggesting a role of SIRT1 in tumor suppression.

The Sirtuin family of proteins (SIRT) encode a group of evolutionarily conserved, NAD-dependent histone deacetylases, involved in many biological pathways. SIRT1, the human homologue of the yeast Silent Information Regulator 2 (Sir2) gene, deacetylates histones, p300, p53, and the androgen receptor. Autophagy is required for the degradation of damaged organelles and long-lived proteins, as well as for the development of glands such as the breast and prostate. Herein, homozygous deletion of the Sirt1 gene in mice resulted in prostatic intraepithelial neoplasia (PIN) associated with reduced autophagy. Genome-wide gene expression analysis of Sirt1(-/-) prostates demonstrated that endogenous Sirt1 repressed androgen responsive gene expression and induced autophagy in the prostate. Sirt1 induction of autophagy occurred at the level of autophagosome maturation and completion in cultured prostate cancer cells. These studies provide novel evidence for a checkpoint function of Sirt1 in the development of PIN and further highlight a role for SIRT1 as a tumor suppressor in the prostate.

SIRT1 is an evolutionarily conserved protein deacetylase that modulates stress response, cellular metabolism and aging in model organisms. While SIRT1 exerts beneficial effects in protecting against age-related diseases, the role of SIRT1 in cancer has been controversial. SIRT1 promotes cell survival by deacetylating, and thereby negatively regulating the activity of important tumor suppressors such as p53. In this regard, SIRT1 has been considered to be a potential oncogene, and SIRT1 inhibitors have been studied for possible anticancer therapeutic effects. In contrast, it has been shown that SIRT1 deficiency leads to increased genomic instability and tumorigenesis, and that overexpression of SIRT1 attenuates cancer formation in mice, suggesting it may also act as a tumor suppressor. Based on this evidence, SIRT1-activating molecules could act as candidate chemotherapeutic drugs. In order to gain insight into the role of SIRT1 in cancer, we performed a comprehensive resequencing analysis of the SIRT1 gene in 41 tumor cell lines and found an unusually excessive homozygosity, which was confirmed to be allelic loss by microsatellite analysis. Furthermore, we found two novel SIRT1 mutations (D739Y and R65_A72del) in addition to the known, rare non-synonymous variation resulting in I731V. In vitro assays using purified SIRT1 protein showed that these mutations do not alter SIRT1 deacetylase activity or telomerase activity, which was shown to be regulated by SIRT1. We conclude that allelic loss or mutations in the SIRT1 gene occur prevalently during tumorigenesis, supporting the assertion that SIRT1 may serve as a tumor suppressor.