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PubMed2005

Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2 cell death.

We previously demonstrated that evodimine isolated from Evodia rutaecarpa (Goshuyu in Japan) induced apoptosis in human malignant melanoma A375-S2 cells within 24 h. In this study, TUNEL assay also indicated that one cause of A375-S2 cell death induced by evodiamine was apoptosis. After treatment with evodiamine for the indicated time periods, anti-apoptotic protein SIRT1 expression was decreased; p53 expression and its phosphorylation were both enhanced, whereas transient induction of downstream p21 was not enough to promote cell cycle arrest. Inhibition of the phosphoinositide 3-OH kinase (PI3-K)/protein kinase C (PKC) survival pathway as well as subsequent inhibition of the ERK cascade might contribute to evodiamine-induced cell death. In addition, p53 activation in response to evodiamine administration was correlated with the activation of the PI3-K/PKC pro-apoptotic pathway, but did not require ERK participation. The inhibition of the PI3-K/PKC survival pathway might be responsible for SIRT1 inactivation and increased Bax/Bcl-2 expression ratio in evodiamine-induced cell death.

Androstadienes↗
PubMed2026

Subcellular sirtuin signaling networks: pivotal regulators of cardiovascular homeostasis and remodeling.

Sirtuins represent a family of highly conserved enzymes, initially identified as Silent Information Regulator 2 (Sir2) in yeast, where they serve as fundamental determinants of longevity. Overexpression of Sir2 in yeast significantly extends lifespan, while its deletion leads to shortened longevity. In mammals, sirtuins (SIRT1-7) represent a conserved family of NAD+-dependent deacylases with diverse catalytic activities. While most members primarily function as deacetylases, SIRT4 exhibits mono-ADP-ribosylation activity, and SIRT5 uniquely targets negatively charged acyl groups, including lysine succinylation, malonylation, and glutarylation. These enzymes act as critical intracellular sensors and regulators widely distributed across diverse tissues. By targeting a broad array of protein substrates, they regulate core biological processes-including genomic stability, metabolism, inflammation, and stress responses. As cardiovascular diseases (CVDs) remain the primary cause of global mortality, driven by complex pathologies such as chronic inflammation and metabolic dysregulation, the sirtuin network has emerged as an indispensable regulator of cardiovascular health. This review systematically elucidates the pivotal roles of sirtuins in cardiovascular homeostasis. We provide an in-depth, subcellular perspective on how nuclear, cytoplasmic, and mitochondrial sirtuins synergistically protect against cardiovascular remodeling, atherosclerosis (AS), and heart failure (HF). Particular emphasis is placed on the molecular mechanisms modulating macrophage polarization and the mitigation of vascular inflammation via the NF-κB signaling pathway. Furthermore, we assess the therapeutic promise of caloric restriction (CR) and pharmacological activators, incorporating recent human clinical evidence. We propose a framework matching sirtuin-based interventions to disease tempo, advocating isoform and compartment-specific strategies for acute and chronic CVDs.

Sirtuins↗
PubMed2005

Increased expression of histone deacetylase 2 is found in human gastric cancer.

Accumulated evidence has established that aberrant regulation of histone deacetylases (HDACs) is one of the major causes of the development of human malignancies. Among different iso-enzymes of HDAC and sirtuins grouped as the HDAC super family, little is known as to how histone deacetylase 2 (HDAC2) causes carcinogenesis in solid tumors. Here, in order to investigate the possible role of HDAC2 in gastric carcinogenesis, we analyzed the expression of HDAC2 in 71 gastric adenocarcinomas by immunohistochemistry. Moderate to strong expression of HDAC2 was found in 44 (62%) out of a total of 71 tumors. The majority of positive tumors, which were detected in the nucleus but not in normal gastric epithelium, did not express HDAC2 or showed only weak positive staining. Interestingly, we also noted that HDAC2 expression appeared to be associated with tumor aggressiveness as HDAC2 expression was observed to be statistically significant in advanced gastric cancer (P=0.0023, Chi-square test) and in positive lymph node metastasis (P=0.0713, Chi-square test). Taken together, these results suggest that HDAC2 may play an important role in the aggressiveness of gastric cancer.

Adenocarcinoma↗
PubMed2006

Worming pathways to and from DAF-16/FOXO.

In Caenorhabditis elegans, the insulin/IGF-1 signaling pathway controls many biological processes such as life span, fat storage, dauer diapause, reproduction and stress response . This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO). DAF-16 also receives input from several other pathways that regulate life span such as the germline and the JNK pathway [Hsin, H., Kenyon, C., 1999. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362-366; Oh, S.W., Mukhopadhyay, A., Svrzikapa, N., Jiang, F., Davis, R.J., Tissenbaum, H.A., 2005. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. USA 102, 4494-4499]. Therefore, DAF-16 integrates signals from multiple pathways and regulates its downstream target genes to control diverse processes. Here, we discuss the signals to and from DAF-16, with a focus on life span regulation.

Aging↗
PubMed2006

Fluorescence in situ hybridization and chromosomal organization of the human Sirtuin 7 gene.

Sirtuin 7 (SIRT7) is a member of the sirtuin family of protein deacetylases and is, therefore, a derivative of yeast Silent information regulator 2 (SIR2). SIR2 and its mammalian orthologs play an important role in epigenetic gene silencing, DNA recombination, cellular differentiation and metabolism, and the regulation of aging. In contrast to most sirtuins, SIRT7 does not exert characteristic NAD+-dependent deacetylase activity. We have isolated and characterized the human Sirt7 genomic sequence, which spans a region of 6.2 kb and which has one single genomic locus. Determination of the exon/intron splice junctions found the full-length SIRT7 protein to consist of 10 exons ranging in size from 71 bp (exon 4) to 237 bp (exon 7). The human Sirt7 open reading frame encodes a 400-aa protein with a predictive molecular weight of 44.9 kDa and an isoelectric point of 9.80. Characterization of the 5' flanking genomic region, which precedes the Sirt7 open reading frame, revealed a TATA- and CCAAT-box less promoter that lacks CpG islands. A number of AML-1 and GATA-x transcription factor binding sites were found, which remain to be further evaluated experimentally. Fluorescence in situ hybridization analysis localized the human Sirt7 gene to chromosome 17q25.3; a region which is frequently affected by chromosomal alterations in acute leukemias and lymphomas. Human SIRT7 appears to be most predominantly expressed in the blood and in CD33+ myeloid bone marrow precursor cells, while the lowest levels are found in the ovaries and skeletal muscle. Functional characteristics of SIRT7 are essentially unknown at present and remain to be further elucidated.

5' Flanking Region↗
PubMed2005

Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival.

SIRT1 is a conserved NAD-dependent deacetylase that regulates life span in accord with nutritional provision. In mammalian cells, SIRT1 also down-regulates stress-induced p53 and FoxO pathways for apoptosis, thus favoring survival under stress. The functioning of SIRT1 under normal, nonstressed conditions of cell growth is unknown. Here we have asked if SIRT1 has the capacity to influence cell viability in the absence of applied stress. For this purpose we used synthetic small interfering RNA to silence SIRT1 gene expression by RNA interference (RNAi). We show that the process of RNAi, by itself, does not affect cell growth and is not sufficient to activate a cellular stress response (indicated by lack of activation of endogenous p53). We also show that, in the absence of applied stress, SIRT1 silencing induces growth arrest and/or apoptosis in human epithelial cancer cells. In contrast, normal human epithelial cells and normal human diploid fibroblasts seem to be refractory to SIRT1 silencing. Combined gene knockout with RNAi cosilencing experiments indicate that SIRT1 and Bcl-2 may suppress separable apoptotic pathways in the same cell lineage and that the SIRT1-regulated pathway is independent of p53, Bax, and caspase-2. Alternatively, SIRT1 may suppress apoptosis downstream from these apoptotic factors. In either case, we show that FoxO4 (but not FoxO3) is required as proapoptotic mediator. We further identify caspase-3 and caspase-7 as downstream executioners of SIRT1/FoxO4-regulated apoptosis. Our work identifies SIRT1 as a novel target for selective killing of cancer versus noncancer epithelial cells.

Apoptosis↗
PubMed2006

Sir2 protein deacetylases: evidence for chemical intermediates and functions of a conserved histidine.

Sir2 NAD+-dependent protein deacetylases are implicated in a variety of cellular processes such as apoptosis, gene silencing, life-span regulation, and fatty acid metabolism. Despite this, there have been relatively few investigations into the detailed chemical mechanism. Sir2 proteins (sirtuins) catalyze the chemical conversion of NAD+ and acetylated lysine to nicotinamide, deacetylated lysine, and 2'-O-acetyl-ADP-ribose (OAADPr). In this study, Sir2-catalyzed reactions are shown to transfer an 18O label from the peptide acetyl group to the ribose 1'-position of OAADPr, providing direct evidence for the formation of a covalent alpha-1'-O-alkylamidate, whose existence is further supported by the observed methanolysis of the alpha-1'-O-alkylamidate intermediate to yield beta-1'-O-methyl-ADP-ribose in a Sir2 histidine-to-alanine mutant. This conserved histidine (His-135 in HST2) activates the ribose 2'-hydroxyl for attack on the alpha-1'-O-alkylamidate. The histidine mutant is stalled at the intermediate, allowing water and other alcohols to compete kinetically with the attacking 2'-hydroxyl. Measurement of the pH dependence of kcat and kcat/Km values for both wild-type and histidine-to-alanine mutant enzymes confirms roles of this residue in NAD+ binding and in general-base activation of the 2'-hydroxyl. Also, transfer of an 18O label from water to the carbonyl oxygen of the acetyl group in OAADPr is consistent with water addition to the proposed 1',2'-cyclic intermediate formed after 2'-hydroxyl attack on the alpha-1'-O-alkylamidate. The effect of pH and of solvent viscosity on the kcat values suggests that final product release is rate-limiting in the wild-type enzyme. Implications of this new evidence on the mechanisms of deacetylation and possible ADP-ribosylation catalyzed by Sir2 deacetylases are discussed.

Acetylation↗
PubMed2004

Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.

A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.

Acetylation↗
PubMed2006

Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1.

Terminally differentiated adult injured cardiac myocytes have been used for various animal models of heart failure. It has recently been shown that isoproterenol induces injury in rat neonatal cardiac myocytes via a beta-adrenergic pathway, suggesting that it might be one of the factors involved in myocardial cell injury in heart failure in vivo. In the study, silibinin, a plant flavanoid from milk thistle was first evaluated for its protective effect against beta-adrenergic agonist isoproterenol-induced injury in cultured rat neonatal cardiac myocytes. The viability, activation of lactate dehydrogenase (LDH), and content of maleic dialdehyde (MDA) were chosen for measuring the degree of cardiac myocytes injury. As a result, silibinin protected isoproterenol-treated rat cardiac myocytes from death and significantly decreased LDH release and MDA production. Silibinin increased superoxide dismutase activity, decreased [Ca(2+)](i), and increased mitochondrial membrane potential (DeltaPsi). Furthermore, the release of pro-apoptotic cytochrome c from mitochondria was reduced by silibinin. Silibinin increased the expression of anti-apoptotic Bcl-2 family protein Bcl-2, and up-regulation of SIRT1 inhibited the translocation of Bax from cytoplasm to mitochondria, which caused mitochondrial dysfunction and cell injury. These results demonstrate that silibinin protects against isoproterenol-induced cardiac myocytes injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.

Adrenergic beta-Agonists↗
PubMed2006

Acetylation of estrogen receptor alpha by p300 at lysines 266 and 268 enhances the deoxyribonucleic acid binding and transactivation activities of the receptor.

Using a variety of biochemical and cell-based approaches, we show that estrogen receptor alpha (ERalpha) is acetylated by the p300 acetylase in a ligand- and steroid receptor coactivator-dependent manner. Using mutagenesis and mass spectrometry, we identified two conserved lysine residues in ERalpha (Lys266 and Lys268) that are the primary targets of p300-mediated acetylation. These residues are acetylated in cells, as determined by immunoprecipitation-Western blotting experiments using an antibody that specifically recognizes ERalpha acetylated at Lys266 and Lys268. The acetylation of ERalpha by p300 is reversed by native cellular deacetylases, including trichostatin A-sensitive enzymes (i.e. class I and II deacetylases) and nicotinamide adenine dinucleotide-dependent/nicotinamide-sensitive enzymes (i.e. class III deacetylases, such as sirtuin 1). Acetylation at Lys266 and Lys268, or substitution of the same residues with glutamine (i.e. K266/268Q), a residue that mimics acetylated lysine, enhances the DNA binding activity of ERalpha in EMSAs. Likewise, substitution of Lys266 and Lys268 with glutamine enhances the ligand-dependent activity of ERalpha in a cell-based reporter gene assay. Collectively, our results implicate acetylation as a modulator of the ligand-dependent gene regulatory activity of ERalpha. Such regulation is likely to play a role in estrogen-dependent signaling outcomes in a variety of estrogen target tissues in both normal and pathological states.

Acetylation↗
PubMed2004

Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.

Calorie restriction extends lifespan in organisms ranging from yeast to mammals. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma), including genes mediating fat storage. Sirt1 represses PPAR-gamma by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). Mobilization of fatty acids from white adipocytes upon fasting is compromised in Sirt1+/- mice. Repression of PPAR-gamma by Sirt1 is also evident in 3T3-L1 adipocytes, where overexpression of Sirt1 attenuates adipogenesis, and RNA interference of Sirt1 enhances it. In differentiated fat cells, upregulation of Sirt1 triggers lipolysis and loss of fat. As a reduction in fat is sufficient to extend murine lifespan, our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals.

3T3-L1 Cells↗
PubMed2006

Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.

We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the activity of a metabolic enzyme by means of reversible lysine acetylation. Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans.

Acetate-CoA Ligase↗
PubMed2003

Propionyl coenzyme A is a common intermediate in the 1,2-propanediol and propionate catabolic pathways needed for expression of the prpBCDE operon during growth of Salmonella enterica on 1,2-propanediol.

The studies reported here identify propionyl coenzyme A (propionyl-CoA) as the common intermediate in the 1,2-propanediol and propionate catabolic pathways of Salmonella enterica serovar Typhimurium LT2. Growth on 1,2-propanediol as a carbon and energy source led to the formation and excretion of propionate, whose activation to propionyl-CoA relied on the activities of the propionate kinase (PduW)/phosphotransacetylase (Pta) enzyme system and the CobB sirtuin-controlled acetyl-CoA and propionyl-CoA (Acs, PrpE) synthetases. The different affinities of these systems for propionate ensure sufficient synthesis of propionyl-CoA to support wild-type growth of S. enterica under low or high concentrations of propionate in the environment. These redundant systems of propionyl-CoA synthesis are needed because the prpE gene encoding the propionyl-CoA synthetase enzyme is part of the prpBCDE operon under the control of the PrpR regulatory protein, which needs 2-methylcitrate as a coactivator. Because the synthesis of 2-methylcitrate by PrpC (i.e., the 2-methylcitrate synthase enzyme) requires propionyl-CoA as a substrate, the level of propionyl-CoA needs to be raised by the Acs or PduW-Pta system before 2-methylcitrate can be synthesized and prpBCDE transcription can be activated.

Acyl Coenzyme A↗
PubMed2026

Fetal hypoxia causes oocyte oxidative stress damage via the Sirt3/Sod2 pathway and can be alleviated by nicotinamide mononucleotide.

Environmental hypoxia exerts detrimental effects on the reproductive capabilities of both humans and animals. A fetal hypoxia model was established in which fetal mice were kept in a high-plateau hypoxic setting from embryonic day (E) 0 to 16.5. In our previous research, we found that fetal hypoxia exposure perturbs the methylation of imprinted genes in adult sperm and causes intergenerational placental impairments in male offspring. However, the specific impacts of fetal hypoxia on the female reproductive system, particularly regarding oocyte maturation, remain poorly understood. First, we found that fetal hypoxia mice exhibited a significant reduction in the average number of pups per litter. We conducted a comprehensive analysis of the transcriptome in oocytes from the hypoxic group and investigated the metabolic alterations within the follicular microenvironment. Fetal hypoxic stress contributed to cleavage and blastocyst rate reduction and induced early apoptosis and DNA damage triggered by mitochondrial dysfunction, oxidative stress aggravation and Sirt3/Sod2 downregulation. Additionally, administration of nicotinamide mononucleotide (NMN) has been shown to prevent oocytes from mitochondrial dysfunction and developmental impairment by increasing the expression of Sirt3/Sod2 and autophagy. The number of pups per litter in fetal hypoxia mice was reduced by 57.7% compared to the control group, while NMN intervention could restore it to 73.1% of the control group. These results indicate that fetal hypoxia exposure exerts multiple potential damages to adult female reproduction, while highlighting the clinical potential of NMN supplementation as a targeted intervention to alleviate such hypoxia-associated female reproductive impairment.

Animals↗
PubMed2002

SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria.

The SIR2 (silent information regulator 2) gene family has diverse functions in yeast including gene silencing, DNA repair, cell-cycle progression, and chromosome fidelity in meiosis and aging. Human homologues, termed sirtuins, are highly conserved but are of unknown function. We previously identified a large imprinted gene domain on 11p15.5 and investigated the 11p15.5 sirtuin SIRT3. Although this gene was not imprinted, we found that it is localized to mitochondria, with a mitochondrial targeting signal within a unique N-terminal peptide sequence. The encoded protein was found also to possess NAD(+)-dependent histone deacetylase activity. These results suggest a previously unrecognized organelle for sirtuin function and that the role of SIRT3 in mitochondria involves protein deacetylation.

Amino Acid Sequence↗
PubMed2005

Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation.

Changes in the substrate specificities of factors that irreversibly modify the histone components of chromatin are expected to have a profound effect on gene expression through epigenetics. Ezh2 is a histone-lysine methyltransferase with activity dependent on its association with other components of the Polycomb Repressive Complexes 2 and 3 (PRC2/3). Ezh2 levels are increasingly elevated during prostate cancer progression. Other PRC2/3 components also are elevated in cancer cells. Overexpression of Ezh2 in tissue culture promotes formation of a previously undescribed PRC complex, PRC4, that contains the NAD+-dependent histone deacetylase SirT1 and isoform 2 of the PRC component Eed. Eed2 is expressed in cancer and undifferentiated embryonic stem (ES) cells but is undetectable in normal and differentiated ES cells. The distinct PRCs exhibit differential histone substrate specificities. These findings suggest that formation of a transformation-specific PRC complex may have a major role in resetting patterns of gene expression by regulating chromatin structure.

Animals↗
PubMed2005

Redox-dependent transcriptional regulation.

Reactive oxygen species contribute to the pathogenesis of a number of disparate disorders including tissue inflammation, heart failure, hypertension, and atherosclerosis. In response to oxidative stress, cells activate expression of a number of genes, including those required for the detoxification of reactive molecules as well as for the repair and maintenance of cellular homeostasis. In many cases, these induced genes are regulated by transcription factors whose structure, subcellular localization, or affinity for DNA is directly or indirectly regulated by the level of oxidative stress. This review summarizes the recent progress on how cellular redox status can regulate transcription-factor activity and the implications of this regulation for cardiovascular disease.

Adaptor Proteins, Signal Transducing↗
PubMed2026

LncRNA RP11-708J19.2 promotes colorectal cancer progression by binding to SIRT7 via regulating H3K18ac.

Colorectal cancer (CRC) is a prevalent malignancy with a complex genetic basis. Recent genome-wide association studies (GWAS) have identified a susceptibility locus at 3p21.31, however, the functional SNP(s) underlying the association between the 3p21.31 region and CRC remain to be elucidated. In this study, we identified rs2101247 as the potential functional SNP and further demonstrated that rs2101247 is significantly associated with the expression of the nearby long non-coding RNA (lncRNA) RP11-708J19.2 (ENSG00000271161.1). Functional experiments showed that RP11-708J19.2 is upregulated in CRC tumor tissues, and its knockdown reduces cell viability while promoting apoptosis in SW1116 and HCT116 cell lines. Mechanistically, RP11-708J19.2 interacts directly with the deacetylase SIRT7, modulating histone H3K18 acetylation (H3K18ac). Specifically, RP11-708J19.2 knockdown leads to a significant upregulation of H3K18ac levels, implicating a SIRT7-mediated epigenetic pathway in CRC progression. Our findings elucidate a novel functional SNP-lncRNA axis that contributes to CRC pathogenesis, providing potential biomarkers for early detection and therapeutic targets for intervention.

Humans↗