SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae))

2014-12-01   WenYong Chen 




SIRT1 is a member of the mammalian sirtuin genes that encode for seven protein lysine modifiers with deacetylase, ADP-ribosyltransferase and other deacylase activities. SIRT1 plays diverse roles in regulating cell proliferation, differentiation, stress response, metabolism, energy homeostasis, aging and cancer. Besides deacetylating histone substrates, SIRT1 regulates functions of an array of non-histone proteins including transcriptional factors for gene regulation, DNA repair machinery elements for reducing catastrophic genome lesions, epigenetic factors for chromatin and gene regulation, nuclear receptors and circadian clock as well as related factors for metabolism, and other cell signaling molecules. SIRT1 is involved in many types of human cancer.


Atlas Image
SIRT1 gene expression is modulated at both transcriptional and posttranscriptional levels.


The SIRT1 gene spans about 34 kb including nine exons. The SIRT1 promoter contains a CCAAT box and a number of NF-kappaB and GATA transcription factor binding sites in addition to a small 350-bp CpG island in the 5 flanking genomic region. The gene encodes a 747 amino acids protein with a predictive molecular weight of 81.7 kDa and an isoelectric point of 4.55 (Alcaín and Villalba, 2009).


SIRT1 transcription is under the control of at least two negative feedback loops that keep its induction tightly regulated under conditions of oxidative stress. SIRT1 promoter can be regulated by E2F1 and HIC1 during cellular stress. E2F1 directly binds to the SIRT1 promoter at a consensus site located at bp position -65 and appears to regulate the basal expression level of SIRT1. Such high levels of SIRT1 lead to a negative feedback loop where E2F1 activity is inhibited by SIRT1-mediated deacetylation. By contrast, the tumor suppressor HIC1 and SIRT1 form a transcriptional repression complex that directly binds SIRT1 promoter and represses SIRT1 transcription thereby inhibiting SIRT1-mediated p53 deacetylation and inactivation. Two HIC1 binding sites have been assigned to base pair positions -1116 and -1039 within the SIRT1 promoter (Chen et al., 2005). In addition, two functional p53 binding sites (-178 bp and -168 bp), which normally repress SIRT1 expression, have been identified. Furthermore, SIRT1 transcription is upregulated by MYC that binds at SIRT1 promoter position -80 and by STAT5 that binds at positions -2235 and -1838 in response to BCR-ABL oncogenic stress (Yuan et al., 2012).
SIRT1 expression is also regulated at the posttranscriptional level by HuR. It has been demonstrated that HuR, a ubiquitously expressed RNA binding protein, associates with the 3 UTR of the SIRT1 mRNA under physiological conditions and helps to stabilize the transcript. This interaction results in increased SIRT1 mRNA stability and thus in elevated protein levels. Conversely, the HuR-SIRT1 mRNA complex is being disrupted upon oxidative stress, which finally leads to decreased mRNA stability and therefore decreased SIRT protein levels. In addition, several microRNA (miR) species negatively regulate SIRT1 mRNA by targeting its 3 UTR, including miR-34a and miR-200a (reviewed in Roth and Chen, 2014).


None identified.


Atlas Image
SIRT1 deacetylase activity is modulated through protein-protein interaction and sumoylation at its three protein domains (Liu T et al., 2009).


Human SIRT1 encodes 747 amino acids protein with a nuclear localization signal (NLS) at the N-terminus (aa 41-46) and a sirtuin homology domain at the center (aa 261-447); this domain is a conserved catalytic domain for deacetylation. The catalytic activity of SIRT1 is dependent on the cofactor nicotinamide adenine dinucleotide (NAD+).


Expression appears to be ubiquitous in adult tissues (although at different levels). Two proteins have been identified to regulate the SIRT1 activity both positively and negatively through complex formation in the context of the cellular stress response. The first identified direct regulator of SIRT1 was the active regulator of SIRT1 (AROS). The AROS protein is known to significantly enhance the activity of SIRT1 on acetylated p53 both in vitro and in cell lines thereby promoting the inhibitory effect of SIRT1 on p53-mediated transcriptional activity of pro-apoptotic genes (e.g. Bax and p21Waf-1) under conditions of DNA-damage. A negative regulator of SIRT1, DBC-1 (deleted in breast cancer-1), has recently been identified. DBC1 binds directly to the catalytic domain of SIRT1, preventing substrate binding to SIRT1 and inhibiting SIRT1 activity. Reduction of DBC1 inhibits p53-mediated apoptosis after induction of double-stranded DNA breaks owing to SIRT1-mediated p53 deacetylation. Both factors represent the first endogenous, direct regulators of SIRT1 function. SIRT1 activity is also regulated by cis-elements of its own peptides. The SIRT1 C-terminal region (aa 631-635) is a disordered domain, and it interacts with SIRT1 catalytic core domain by competing with DBC1 and activates SIRT1 activity (Kang et al., 2011). A small rigid region at the N-terminus (aa 190-244) of SIRT1 appears to mediates allosteric activators for the SIRT1 catalytic core function (Hubbard et al., 2013). In addition, SIRT1 activity is subjected to regulation by other posttranslational modifications such as sumoylation, phosphorylation and methylation in response to stress signaling and cell cycle changes (reviewed in Wang and Chen, 2013). As an NAD-dependent enzyme, SIRT1 activity is regulated by cellular NAD metabolism in which NAD salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) is often co-activated with SIRT1 to maintain the deacetylase activity (Wang et al., 2011; Menssen et al., 2012).


SIRT1 is predominately in the nucleus (although SIRT1 does have some important cytoplasmic functions as well). In addition to possessing two NLSs, SIRT1 contains two nuclear export signals. Thus, the exposure of nuclear localization signals versus nuclear export signals may dictate the cytosolic versus nuclear localization of SIRT1.


SIRT1 has been reported to play a key role in a variety of physiological processes such as metabolism, neurogenesis and cell survival due to its ability to deacetylate both histone and numerous nonhistone substrates.
(1) Lysines 9 and 14 in the amino-terminal tail of histone H3 and lysine 16 of histone H4 are deacetylated by yeast Sir2 and mammalian SIRT1 (Sir2alpha).
(2) Metabolic homeostasis is controlled by SIRT1-mediated deacetylation and thus activation of the peroxisome proliferation activating receptor (PPAR)-gamma co-activator-1a (PGC-1a), which stimulates mitochondrial activity and subsequently increases glucose metabolism, which in turn improves insulin sensitivity. SIRT1 represses PPAR-gamma, a key regulator of adipogenesis, by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). The upregulation of SIRT1 triggers lipolysis and loss of fat.
(3) The activation of SIRT1 appears to be neuroprotective in animal models for Alzheimers disease and amyotrophic lateral sclerosis as well as optic neuritis mainly due to decreased deacetylation of the tumor suppressor p53 and PGC-1a.
(4) SIRT1 represses p53-dependent apoptosis in response to DNA damage and oxidative stress and promotes cell survival under cellular stress induced by etoposide treatment or irradiation.
(5) SIRT1 activates FOXO1 and FOXO4, which promote cell-cycle arrest by inducing p27kip1; SIRT1 also induces cellular resistance to oxidative stress by increasing the levels of manganese superoxide dismutase and GADD45 (growth arrest and DNA damage-inducible protein 45).
(6) SIRT1 inhibits the transcriptional activity of NF-kappaB by deacetylating NF-kappaBs subunit, RelA/p65, at lysine 310. Thus, although SIRT1 is capable of protecting cells from p53-induced apoptosis, it may augment apoptosis by repressing NF-kappaB. SIRT1 is reported to bind CTIP2 (BCL11B B-cell CLL/lymphoma 11B) and accelerate the transcriptional repression by this molecule. CTIP2 represses the transcription of its target genes and is implicated in hematopoietic cell development.
(7) SIRT1 deacetylates and activates functions of several DNA repair factors, including KU70, NBS1, APE1, XPA/C and WRN for multiple DNA damage repair pathways to cope with genotoxic stress. Stimulated repair may help cells avoid catastrophic genomic events and survive the damage.
(8) SIRT1 is involved in epigenetic regulation of genes and chromatin. SIRT1 deacetylates several histone tail lysines: histone H4 lysine 16 (H4K16), histone H3 K9 and K14, and histone H1 K26. These modifications of histone tails are closely related to gene silencing and heterochromatin formation that may underlie certain biological processes. SIRT1 can deacetylate DNA methyltransferase 1 (DNMT1) and can either enhance or hinder its methyltransferase activity, thus indirectly affecting global or local DNA methylation patterns. SIRT1 is a component of the polycomb repressor complex (PRC) that is involved in silencing genes during normal development. SIRT1 directly complexes with EZH2, a H3K27 methyltransferase within PRC II complex, and is an integral part of the PRCs silencing functions. A SIRT1-containing PRC complex, termed PRC4, is specifically found in transformed cells and embryonic stem cells. In addition, SIRT1 interacts and deacetylates the SUV39H1 methyltransferase, promoting histone H3 methylation and fostering heterochromatin formation, and repressing rRNA transcription to protect cells from energy deprivation-dependent apoptosis (reviewed in Roth and Chen, 2014).


SIRT1 is the mammalian homologue closest to yeast NAD+-dependent deacetylase Sir2 (silent information regulation 2). It was originally identified as a lifespan extending gene when over-expressed in budding yeast, Caenorhabditis elegans, and Drosophila melanogaster. The SIR2 gene is broadly conserved in organisms ranging from bacteria to humans. The accession numbers for the amino acid sequences used are as follows: yeast Sir2 (CAA25667), mouse Sir2alpha (AAF24983), human Sirt1 (AAD40849). All of the sirtuin proteins contain the ~275 residue sirtuin homology domain. In many instances a highly conserved protein domain represents a conserved functional binding site for a metabolite or biomolecule and such conserved binding site domains are often found within enzymatic catalytic domains.



A germ line mutation L107P of SIRT1 was found in a family with type I diabetes. Expression of this mutant SIRT1 in insulin-producing cells stimulated production of nitric oxide, cytokines and chemokines, and decreased anti-inflammatory activity of pancreatic beta cells (Biason-Lauber et al., 2013).


A small number of SIRT1 somatic mutations were registered in human cancer databases but the mutation rate is typically very low (

Implicated in

SIRT1 plays an important role in drug resistance of chronic myelogenous leukemia (CML).
CML is a lethal malignant disease of hematopoietic stem cells. It is caused by reciprocal translocation of chromosomes 9 and 22, producing BCR-ABL fusion gene. BCR-ABL protein has aberrant tyrosine kinase activity and predominantly resides in the cytoplasm in contrast to predominantly nuclear localization of ABL protein. CML progresses from chronic phase to accelerated phase and blast crisis with increasing numbers of blast cells in bone marrow and blood. SIRT1 is activated by BCR-ABL oncogenic transformation in human CML stem/progenitor cells (Yuan et al., 2012; Li et al., 2012).
CML in chronic phase can be effectively treated tyrosine kinase inhibitors such as first-line drug imatinib, and second-line drugs nilotinb and dasatinib, which results in the five-year survival rate over 85%. However, the residual disease persists as these drugs do not eradicate CML leukemic stem cells, and the disease relapses if the drug is ceased. CML in advanced phases has much poorer prognosis and the disease typically relapses quickly on tyrosine kinase inhibitor treatment since the cells acquire BCR-ABL mutations that block the binding of the drugs to BCR-ABL.
Philadelphia chromosome, t(9;22) translocation.
Fusion protein
BCR-ABL fusion protein with aberrant tyrosine kinase activity.
BCR-ABL transformation activates SIRT1 gene expression in both tyrosine kinase-dependent and independent manners, with the former mediating via STAT5 that binds on the SIRT1 promoter to stimulate the transcription. The mechanism for the kinase-independent SIRT1 activation is unknown. SIRT1 knockout significantly blocks BCR-ABL mediated leukemogenesis in a mouse model study (Yuan et al., 2012). Since blocking BCR-ABL kinase activity only partially reduces SIRT1 expression and the pathway remains active, SIRT1 inhibition sensitizes human CML leukemia stem cells to tyrosine kinase inhibitors and helps eradicate these cells by increasing p53 acetylation and activating p53 downstream target gene expression (Li et al., 2012). In addition, SIRT1 promotes acquisition of resistant BCR-ABL mutations for disease relapse in association with its ability to deacetylate and activate KU70 for increased error-prone DNA damage repair in blast crisis CML cells (Wang et al., 2013). Targeting SIRT1 may have clinical implication to improve CML treatment.
SIRT1 plays an important role in drug resistance of acute myeloid leukemia (AML) with FLT-ITD mutation.
AML is a group of highly heterogenous myeloid leukemia with distinct oncogenic events including various chromosomal aberrations and mutations. AML is generally derived from myeloid progenitor cells. SIRT1 protein expression is more consistently increased in AML samples, particularly those harboring FLT-ITD alteration. The change of SIRT1 mRNA is less consistent in certain AML subcategories from one to another study (Sasca et al., 2014; Li et al., 2014).
AML with FLT-ITD mutation has poor prognosis.
Fusion protein
FLT-ITD has constitutively activated tyrosine kinase activity.
Similar to BCR-ABL transformation of hematopoietic stem cells, SIRT1 expression change in AML cells is likely a result of cellular response to oncogenic stress. However, protein regulation of SIRT1 appears more important in the AML setting. SIRT1 protein is stabilized by USP22, a deubiquitinase that is induced by c-MYC in FLT-ITD AML cells (Li et al., 2014). In addition, SIRT1 activity is further regulated by ATM-DBC1 in a FLT-ITD dependent manner (Sasca et al., 2014). Inhibition of SIRT1 sensitizes FLT-ITD AML stem/progenitor cells to tyrosine kinase inhibitor treatment, and may help improve management of this category of AML.
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In large B-cell lymphoma patients, positive expression of SIRT1 protein was seen in 74% of patients, and significantly associated with shorter overall survival. Inhibition of SIRT1/2 by Cambinol induces apoptosis in Burkitt lymphoma cells (reviewed in Yuan et al., 2013).
Large B-cell lymphoma with SIRT1 upregulation showed poor prognosis.
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Lung cancer
Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 (deleted in breast cancer 1) control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma. The lung squamous cell carcinoma patients with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation HIC1-SIRT1-p53 circular loop in clinical model. Expression of DBC1, which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in lung adenocarcinoma patients.
Lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis.
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Breast cancer
The breast cancer associated protein, BCA3, when neddylated (modified by NEDD8) interacts with SIRT1 and suppresses NF-kB-dependent transcription, also sensitizes human breast cancer cells (such as MCF7) to TNF-a-induced apoptosis. In addition, it has been shown recently that SIRT7 levels of expression increase significantly in breast cancer, and that SIRT7 and SIRT3 both are highly transcribed in lymph-node positive breast biopsies, a stage in which the tumour size is at least 2 mm and the cancer has already spread to the lymph nodes. SIRT1 up-regulation is also associated with decreased miR-200a in breast cancer samples, which targets the 3UTR of SIRT1 mRNA and promotes epithelial-mesenchymal transition (EMT)-like transformation in mammary epithelial cells. SIRT1 is essential for oncogenic signaling of estrogen/estrogen receptor α (ERα) in breast cancer. SIRT1 inactivation suppresses estrogen/ERα-induced cell growth and tumor development, and induces apoptosis. SIRT1 is found to be significantly up-regulated in the invasive ductal carcinoma, and positively regulates the expression of aromatase, an enzyme responsible for a key step in the biosynthesis of estrogen in breast cancer. However, in HMLER breast cancer cells, SIRT1 was found to suppress EMT, and reduced SIRT1 expression increases metastasis of these cells in nude mice (reviewed in Yuan et al., 2013).
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Prostate cancer
SIRT1 is significantly overexpressed in primary human prostate cancer tissues and cell lines. SIRT1 inhibition via nicotinamide, sirtinol, short hairpin RNAs or mutation of the 25 amino acid C-terminal SIRT1 activator sequence, results in a significant inhibition of prostate cancer cell growth, viability and chemoresistance. SIRT1 is highly expressed in advanced prostate cancer tissues and promotes prostate cancer cell invasion, migration and metastasis through MMP2, EMT inducing transcription factor ZEB1, and cortactin. Concomitant with SIRT1 activation, NAMPT is over-expressed in prostate cancer, likely enabling supply of NAD+ for SIRT1 functions. In the transgenic mouse model, SIRT1 expression promotes murine prostate carcinogenesis initiated by Pten-deficiency (reviewed in Yuan et al., 2013).
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Liver cancer
SIRT1 expression is significantly elevated in hepatocellular carcinoma (HCC) tissues, and the expression levels correlate with tumor grades and predict poor prognosis. SIRT1 expression also positively correlates with c-MYC levels in HCC. SIRT1 and c-MYC regulate each other via a positive feedback loop and act synergistically to promote cell proliferation of both mouse and human liver tumor cells. SIRT1 promotes tumorigenesis and chemoresistance in HCC, and inhibition of SIRT1 suppresses the proliferation of HCC cells in vitro or in vivo via the induction of cellular senescence or apoptosis. Accordingly, expression of miRNA-34a is reduced in HCC, and the reduced expression of miRNA-34a is associated with worse outcome of HCC patients. Treatment of established HCC xenograft with miR-34a-expressing adenovirus in a mouse model results in complete tumor regression without recurrence (reviewed in Yuan et al., 2013).
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Gastric cancer
SIRT1 protein expression in gastric cardiac carcinoma is significantly higher than that in normal gastric tissues and is associated with lymphatic metastasis, TNM [the extent of tumor (T), the extent of spread to lymph nodes (N), and the presence of distant metastasis (M)] stage, survival rate and mean survival time. In another study, positive expression of SIRT1 was seen in 73% of gastric cancer patients. SIRT1 expression is also significantly associated with shorter overall survival and relapse-free survival. SIRT1 is required for activating transcription factor 4 (ATF4)-induced multidrug resistance in gastric cancer cells. ATF4 facilitates multidrug resistance in gastric cancer cells through direct binding to SIRT1 promoter and activating SIRT1 expression. Significantly, inhibition of SIRT1 by RNAi or a specific inhibitor (EX-527) sensitizes gastric cancer cells to therapeutic treatment (reviewed in Yuan et al., 2013).
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Pancreatic cancer
SIRT1 overexpression was observed in pancreatic cancer tissues at both mRNA and protein levels. Increased SIRT1 positivity is associated with patients age (over 60 years old), larger tumor size (larger than 4 cm), and higher TNM stage. SIRT1 knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells. In pancreatic cancer, SIRT1 regulates ADM (acinar-to-ductal metaplasia) and supports cancer cell viability through deacetylating pancreatic transcription factor-1a and β-catenin. Inhibition of SIRT1 is effective in suppression of ADM and in reducing cell viability in established pancreatic ductal adenocarcinoma. In addition, SIRT1 promotes EMT ability as well as invasion of pancreatic cancer cell by forming a complex with Twist and MBD1 thus suppressing E-cadherin transcription activity. However, one study showed that SIRT1 inhibits proliferation of pancreatic cancer cells expressing oncogenic pancreatic adenocarcinoma up-regulated factor (PAUF), by suppression of β-catenin and cyclin-D1 (reviewed in Yuan et al., 2013).
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Thyroid cancer
SIRT1 is overexpressed in human thyroid cancers and it is positively correlated with c-MYC protein levels. Transgenic SIRT1 expression promotes murine thyroid carcinogenesis initiated by Pten-deficiency. SIRT1 increases c-MYC transcription and stabilizes c-MYC protein in thyroid cancers from SIRT1 transgenic mice or cultured thyroid cancer cells (reviewed in Yuan et al., 2013).
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Colon cancer
Highly-expressed c-MYC correlates with increased SIRT1 protein level in colorectal cancer. In 121 colorectal serrated lesions, the higher expression of c-MYC and SIRT1 protein is strongly associated with higher grades of malignancy. In another study with a total of 485 colorectal cancer patients, SIRT1 overexpression was detected in 180 (37%) tumors. SIRT1 expression is associated with microsatellite instability and CpG island methylator phenotype, although not patient prognosis. Reduced expression of miR-34a, a negative regulator of SIRT1 mRNA, is observed in drug-resistant DLD-1 colon cancer cells, and introduction of miR-34a induces apoptosis by downregulating SIRT1. However, one study showed that in colorectal adenocarcinoma, SIRT1 overexpression was observed in approximately 25% of stage I/II/III tumors but rarely in advanced stage IV tumors. Approximately 30% of carcinomas showed lower SIRT1 expression than normal tissues. In another clinical observation, SIRT1 protein expression is gradually decreased during the normal-adenoma-adenocarcinoma-metastasis stage in colorectal cancers, with the positivity 100%, 80.8%, 41.9%, and 35.7%, respectively (reviewed in Yuan et al., 2013).
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Ovarian cancer
Expression of SIRT1 protein is significantly increased in malignant ovarian epithelial tumors compared to that in benign and borderline epithelial tumors. High proportion (86%) of serous ovarian cancer expressed SIRT1. Interestingly, increased SIRT1 protein in serous ovarian epithelial cancer was associated with increased overall survival (Jang et al., 2009).
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Brain tumor
In glioblastoma, SIRT1 is highly expressed in tumor-derived CD133+ progenitor cells compared to CD133-cells and knockdown of SIRT1 expression enhances the radio-sensitivity and radiation-induced apoptosis in the CD133+ cells. SIRT1 is also frequently expressed in human medulloblastomas relative to surrounding noncancerous cerebellar tissues and its expression is correlated with the formation and prognosis of medulloblastomas. SIRT1 and N-MYC form a positive feedback regulation loop during the tumorigenesis of neuroblastoma, and preventive treatment with the SIRT1 inhibitor Cambinol significantly reduces tumorigenesis in N-MYC transgenic mice (reviewed in Yuan et al., 2013).
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Soft tissue sarcoma
SIRT1 is frequently over-expressed in soft tissue neoplasms with myoid differentiation including angiomyolipoma (4 out of 4 patients), glomus tumor (5 out of 5 patients), leiomyoma (9 out of 10 patients), leiomyosarcoma (76.5% of 51 patients), and rhabdomyosarcoma (87% of 24 patients), and thus could be a potential immunohistochemical marker and therapeutic target in these tumors (reviewed in Yuan et al., 2013).
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Kidney diseases
SIRT1 attenuates TGF-beta (transforming growth factor-beta) apoptotic signaling that is mediated by the effector molecule Smad7. SIRT1-dependent deacetylation of Smad7 at Lys60 and Lys70 enhances its ubiquitin-dependent proteasomal degradation via Smurf1 (Smad ubiquitination regulatory factor 1), thus protecting glomerular mesangial cells from TGF-beta-dependent apoptosis. As a result, SIRT1 expression tends to have protective roles in diabetic kidney disease and excessive inflammatory response triggered by bacterial endotoxins. However, SIRT1 inhibition was found to delay kidney cyst formation in autosomal-dominant polycystic kidney disease through regulating Rb and p53 in cystic renal epithelial cells (Zhou et al., 2013).
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Cardiac hypertrophy
Decreasing hypertrophy or apoptosis in cardiac myocytes can ameliorate the disease, and there is reason to suspect that SIRT1 activation may be useful in this regard. SIRT1 protects primary cultured myocytes from programmed cell death induced by serum starvation or by the activation of PARP-1 [poly(ADP-ribose) polymerase-1] in a p53-dependent manner. SIRT1 also deacetylates Lys115 and Lys121 of the histone variant H2A.Z, a factor known to promote cardiac hypertrophy. In doing so, SIRT1 promotes the ubiquitination and proteosome-dependent degradation of H2A.Z, which may help to protect against heart failure. However, in mouse models it was found that SIRT1 haploinsufficiency attenuates pressure overload-induced cardiac hypertrophy and heart failure (Oka et al., 2011). Contributing to this effect, SIRT1, coordinated by PPARα, suppresses genes involved in mitochondrial functions. In a separate study, cardiac hypertrophy is reduced in Sirt1 deficient mice in response to physical exercise and angiotensin II due to impaired Akt activation as a result of its acetylation (Sundaresan et al., 2011).


Pubmed IDLast YearTitleAuthors
173176272007Phosphorylation of HuR by Chk2 regulates SIRT1 expression.Abdelmohsen K et al
194419042009Sirtuin inhibitors.Alcaín FJ et al
154863192004Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes.Alcendor RR et al
170037812006Altered sirtuin expression is associated with node-positive breast cancer.Ashraf N et al
234730372013Identification of a SIRT1 mutation in a family with type 1 diabetes.Biason-Lauber A et al
112893082001HuR and mRNA stability.Brennan CM et al
191320072009How does SIRT1 affect metabolism, senescence and cancer?Brooks CL et al
222492562012SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis.Byles V et al
191668202009Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression.Chang CJ et al
166873932006Histone H2A.z is essential for cardiac myocyte hypertrophy but opposed by silent information regulator 2alpha.Chen IY et al
162693352005Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.Chen WY et al
152204712004Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.Daitoku H et al
215967532011miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells.Eades G et al
103813781999Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity.Frye RA et al
191737422009Zyxin is a novel interacting partner for SIRT1.Fujita Y et al
169984742006Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription.Gao F et al
111393312001The human histone deacetylase family.Gray SG et al
200782212010Mammalian sirtuins: biological insights and disease relevance.Haigis MC et al
229865352013SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency.Herranz D et al
129630262003Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene.Hiratsuka M et al
160067432005Transcriptional regulation of neuronal genes and its effect on neural functions: NAD-dependent histone deacetylase SIRT1 (Sir2alpha).Hisahara S et al
233402542013SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression.Holloway KR et al
234714112013Evidence for a common mechanism of SIRT1 regulation by allosteric activators.Hubbard BP et al
176388712007SIRT1 is significantly elevated in mouse and human prostate cancer.Huffman DM et al
106938112000Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase.Imai S et al
169091072007SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress.Inoue T et al
194048502009Expression and prognostic significance of SIRT1 in ovarian epithelial tumours.Jang KY et al
105214011999The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.Kaeberlein M et al
220178692011Peptide switch is essential for Sirt1 deacetylase activity.Kang H et al
175816372007SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.Kim D et al
179642662007Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity.Kim EJ et al
182355012008DBC1 is a negative regulator of SIRT1.Kim JE et al
160127552005SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress.Kobayashi Y et al
170987452007SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation.Kume S et al
252802192014SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.Li L et al
223405982012Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib.Li L et al
192441122009The critical role of the class III histone deacetylase SIRT1 in cancer.Liu T et al
116725222001Negative control of p53 by Sir2alpha promotes cell survival under stress.Luo J et al
216981332011SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.Marshall GM et al
221904942012The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop.Menssen A et al
174478942007Sirtuins in mammals: insights into their biological function.Michan S et al
184858712008Epigenetic control of rDNA loci in response to intracellular energy status.Murayama A et al
220555032011PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.Oka S et al
219472822011SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.Peng L et al
151757612004Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.Picard F et al
162077122005Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity.Pillai JB et al
157443102005Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.Rodgers JT et al
236041202014Sorting out functions of sirtuins in cancer.Roth M et al
248552082014SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.Sasca D et al
167564982006The biochemistry of sirtuins.Sauve AA et al
129308292003Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression.Senawong T et al
176527292007SIRT1 activation confers neuroprotection in experimental optic neuritis.Shindler KS et al
172830662007An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.Stankovic-Valentin N et al
217752852011The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.Sundaresan NR et al
171977032007Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1.Tanno M et al
196492062009Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients.Tseng RC et al
180043852007SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation.Vaquero A et al
116725232001hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.Vaziri H et al
163280122006Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1.Voelter-Mahlknecht S et al
209569372011NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response.Wang B et al
168920512006Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.Wang C et al
240199982013Emerging Roles of SIRT1 in Cancer Drug Resistance.Wang Z et al
224107792013SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.Wang Z et al
187558972008miR-34a repression of SIRT1 regulates apoptosis.Yamakuchi M et al
179344532007SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress.Yang Y et al
151521902004Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.Yeung F et al
241333722013The emerging and diverse roles of sirtuins in cancer: a clinical perspective.Yuan H et al
222077352012Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis.Yuan H et al
182355022008Negative regulation of the deacetylase SIRT1 by DBC1.Zhao W et al
237781432013Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease.Zhou X et al
187747772008SIRTUIN 1: regulating the regulator.Zschoernig B et al
151265062004FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).van der Horst A et al

Other Information

Locus ID:

NCBI: 23411
MIM: 604479
HGNC: 14929
Ensembl: ENSG00000096717


dbSNP: 23411
ClinVar: 23411
TCGA: ENSG00000096717


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Amphetamine addictionKEGGhsa05031
Amphetamine addictionKEGGko05031
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
FoxO signaling pathwayKEGGhsa04068
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Glucagon signaling pathwayKEGGhsa04922
Glucagon signaling pathwayKEGGko04922
Gene ExpressionREACTOMER-HSA-74160
Epigenetic regulation of gene expressionREACTOMER-HSA-212165
Negative epigenetic regulation of rRNA expressionREACTOMER-HSA-5250941
SIRT1 negatively regulates rRNA ExpressionREACTOMER-HSA-427359
Circadian ClockREACTOMER-HSA-400253
RORA activates gene expressionREACTOMER-HSA-1368082
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
Regulation of HSF1-mediated heat shock responseREACTOMER-HSA-3371453
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
171125762006Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.1221
149762642004Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.1077
151521902004Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.802
116725222001Negative control of p53 by Sir2alpha promotes cell survival under stress.744
152054772004Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.637
187558972008miR-34a repression of SIRT1 regulates apoptosis.467
149802222004Mammalian SIRT1 represses forkhead transcription factors.449
182966412008A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.446
175816372007SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.363
122975022002Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1.335


WenYong Chen

SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae))

Atlas Genet Cytogenet Oncol Haematol. 2014-12-01

Online version:

Historical Card

2010-03-01 SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) by  Ruo-Chia Tseng,Yi-Ching Wan 

Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC