Sirtuins: critical regulators at the crossroads between cancer and aging

Saunders, Laura R.; Verdin, Eric

doi:10.1038/sj.onc.1210616

Cited by 540 publications

(475 citation statements)

References 149 publications

(239 reference statements)

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“…There is also a therapeutic interest in the sirtuins as they have been linked to the correlation between caloric restriction and life span extension in model organisms such as yeast, worms, flies, fish and rodents; in mammals, sirtuin activity has been linked to counteracting age-associated diseases such as type II diabetes, obesity and neurodegenerative disorders (Wood et al, 2004a, b;Kobayashi et al, 2005;Parker et al, 2005;Anekonda and Reddy, 2006;Baur et al, 2006). The association of sirtuins with aging and diseases is discussed in greater detail in this issue of Oncogene (Saunders and Verdin, 2007). Interestingly, several HDACs have been shown to target non-histone proteins for deacetylation as well.…”

Section: Overview Of Hdacsmentioning

confidence: 99%

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

2007

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The post-translational modification of histones plays an important role in chromatin regulation, a process that insures the fidelity of gene expression and other DNA transactions. Of the enzymes that mediate post-translation modification, the histone acetyltransferase (HAT) and histone deacetylase (HDAC) proteins that add and remove acetyl groups to and from target lysine residues within histones, respectively, have been the most extensively studied at both the functional and structural levels. Not surprisingly, the aberrant activity of several of these enzymes have been implicated in human diseases such as cancer and metabolic disorders, thus making them important drug targets. Significant mechanistic insights into the function of HATs and HDACs have come from the X-ray crystal structures of these enzymes both alone and in liganded complexes, along with associated enzymatic and biochemical studies. In this review, we will discuss what we have learned from the structures and related biochemistry of HATs and HDACs and the implications of these findings for the design of protein effectors to regulate gene expression and treat disease.

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Section: Overview Of Hdacsmentioning

confidence: 99%

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

2007

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“…Sirtuins are a family of protein deacetylases and adenosine diphosphate (ADP)-ribosyltransferases whose functions require NAD þ (Saunders and Verdin, 2007). Among them, SIRT1 has the highest homology to yeast Sir2 (silent information regulator 2) that extends lifespan under calorie restriction (Lin et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD þ ) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD þ -dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H 2 O 2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

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“…the role of sIrt1 in cell survival is achieved by deacetylation of key cell cycle molecules and apoptosis regulatory proteins, including Foxo family proteins (3), Ku70 (4), NF-κB (5), and p53 (6,7). Up-regulation of sIrt1 induces deacetylated inactivation of p53, which allows proliferation of cells in the presence of damaged DNA such that mutations accumulate, including those in p53 itself, leading to disruption of the cell cycle control and promotion of tumor progression (6)(7)(8)(9)(10)(11). recent studies have demonstrated overexpression of sIrt1 in cancer tissue, compared with normal tissue, suggesting that sIrt1 may act as a tumor promoter (9,(12)(13)(14)(15)(16).…”

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confidence: 99%

Expression and role of SIRT1 in hepatocellular carcinoma

Choi

Bae²,

Jamiyandorj³

et al. 2011

Oncol Rep

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Abstract. silent mating type information regulation 2 homolog 1 (sIrt1) is a multifaceted, nicotinamide adenine dinucleotide-dependent protein deacetylase with involvement in a wide variety of cellular processes ranging from cancer to aging. expression of sIrt1 was evaluated in 90 cases of hepatocellular carcinoma (HCC) and five HCC cell lines. The relationship between the mutation status of p53 and expression of sIrt1 was also investigated in 10 fresh HCC tissues. synthetic small interfering rNA was used to silence sIrt1 gene expression by rNA interference (rNAi), and cell growth and cell cycle progression were assessed. expression of sIrt1 was significantly elevated in the HCC tissues when compared to that of non-tumor tissues (p<0.001). Overexpression of sIrt1 and p53 was observed in 56% (50 of 90) and in 30% (27 of 90) of the HCCs, respectively. expression of sIrt1 showed significant correlation with gender (p=0.023), serum AFP levels (p=0.030), viral infection (p=0.005) and p53 expression (p<0.021). Western blot analysis found no correlation between p53 mutation and expression levels of sIrt1. sIrt1 silencing was found to induce cell growth arrest in HCC cells. these results suggest an association of sIrt1 expression with HCC development and that sIrt1 plays a role in cancer cell growth.

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Sirtuins: critical regulators at the crossroads between cancer and aging

Cited by 540 publications

References 149 publications

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

Expression and role of SIRT1 in hepatocellular carcinoma

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