Member Of Sirtuin Family Research Articles

A variant in SIRT2 gene 3'-UTR is associated with susceptibility to colorectal cancer.

SIRT2 is a member of sirtuin family and is associated with cell growth in various cancers. In this study, we searched for variants in functional region of SIRT2 gene and identify rs2015 and rs2241703 in the 3′UTR with minor allele frequency >0.05 in Chinese Han Beijing population from 1000 Genomes Project. We then genotyped these two variants in 842 colorectal cancer (CRC) patients and 1,718 healthy controls using Taqman genotyping assay. Association between variants and risk of CRC is calculated using logistic regression adjusted for sex and age. We found that rs2015C was significantly associated with increased risk of CRC. Compared with CC genotype carriers, CA genotype and AA genotype carriers were associated with CRC susceptibility with OR being 0.79 (95% CI: 0.65–0.96, P = 0.019) and 0.73 (95% CI: 0.58–0.92, P = 0.009), respectively. When stratified by sex and age, significant associations were observed only in males (OR = 0.82, 95% CI: 0.71–0.96, P = 0.010) for rs2015, but not females (OR = 0.90, 95% CI: 0.73–1.10, P = 0.287). It is suggested that the sequence including rs2015C allele lies within a binding site for the full seed region of hsa-miR-376a-5p. Through a systematic interrogate of variants in the functional region of SIRT2 gene, we identified rs2015 was significantly associated with CRC susceptibility, providing new insights into the carcinogenesis of CRC.

Functional genetic variants within the SIRT2 gene promoter in acute myocardial infarction.

Coronary artery disease (CAD), including acute myocardial infarction (AMI) is the complication of atherosclerosis. Recently, genome-wide association studies have identified a large number of CAD-related genetic variants. However, only 10% of CAD cases could be explained. Low frequent and rare genetic variants have been recently proposed to be main causes for CAD. SIRT2 is a member of sirtuin family, NAD(+)-dependent class III deacetylases. SIRT2 is involved in genomic stability, metabolism, inflammation, oxidative stress and autophagy, as well as in platelet function. Thus, we hypothesized that genetic variants in SIRT2 gene may contribute to AMI. In this study, SIRT2 gene promoter was analyzed in large cohorts of AMI patients (n = 375) and ethnic-matched controls (n = 377). Three novel heterozygous DSVs (g.38900888_91delTAAA, g.38900270A>G and g.38899853C>T) were identified in three AMI patients, but in none of controls. These DSVs significantly altered the transcriptional activity of the SIRT2 gene promoter (P<0.05) in both HEK-293 and H9c2 cells. Five novel heterozygous DSVS (g.38900562C>T, g.38900413A>C, g.38900030G>A, g.38899925A>C and g.38899852C>T) were only found in controls, which did not significantly affected SIRT2 gene promoter activity (P>0.05). In addition, four novel heterozygous DSVs and five SNPs were found in both AMI patients and control with similar frequencies (P>0.05), two SNPs of which were examined and did not affect SIRT2 gene promoter activity (P>0.05). Taken together, the DSVs identified in AMI patients may change SIRT2 level by affecting the transcriptional activity of SIRT2 gene promoter, contributing to the AMI development as a rare risk factor.

Fabp4-Cre-mediated Sirt6 deletion impairs adipose tissue function and metabolic homeostasis in mice.

SIRT6 is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis and anti-inflammation. However, its function in the adipose tissue is not well understood. To examine the metabolic function of SIRT6 in the adipose tissue, we generated two mouse models that are deficient in Sirt6 using the Cre-lox approach. Two commonly used Cre lines that are driven by either the mouse Fabp4 or Adipoq gene promoter were chosen for this study. The Sirt6-knockout mice generated by the Fabp4-Cre line (Sirt6f/f:Fabp4-Cre) had a significant increase in both body weight and fat mass and exhibited glucose intolerance and insulin resistance as compared with the control wild-type mice. At the molecular levels, the Sirt6f/f :Fabp4-Cre-knockout mice had increased expression of inflammatory genes including F4/80, TNFα, IL-6 and MCP-1 in both white and brown adipose tissues. Moreover, the knockout mice showed decreased expression of the adiponectin gene in the white adipose tissue and UCP1 in the brown adipose tissue, respectively. In contrast, the Sirt6 knockout mice generated by the Adipoq-Cre line (Sirt6f/f :Adipoq-Cre) only had modest insulin resistance. In conclusion, our data suggest that the function of SIRT6 in the Fabp4-Cre-expressing cells in addition to mature adipocytes plays a critical role in body weight maintenance and metabolic homeostasis.

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct of in vivo studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM (i.e., in high-fat-diet-fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first in vivo study of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.-Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.

Sirtuins and DNA damage repair: SIRT7 comes to play

ABSTRACTAging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress. We recently reported that SirT7−/− mice suffer from partial embryonic lethality and a progeroid like phenotype. At the cellular level, SIRT7 depletion results in the impaired repair of DNA double-strand breaks (DSBs), one the most dangerous DNA lesions, leading to genome instability. SIRT7 is recruited to DSBs, where it specifically deacetylates histone H3 at lysine 18 and affects the focal accumulation of the DNA damage response factor 53BP1, thus influencing the efficiency of repair. Here, we integrate our findings with the current knowledge on the mode of action of other sirtuin family members in DNA repair. We emphasize their capacity to regulate chromatin structure as a response to DNA damage within the constraints imposed by cellular status.

Sirtuin 3 is required for osteogenic differentiation through maintenance of PGC-1ɑ-SOD2-mediated regulation of mitochondrial function.

Osteogenic differentiation is crucial for the maintenance of bone homeostasis. Sirtuin 3 (SIRT3), a member of sirtuins family, functions as a critical deacetylase that regulates many key proteins. In the current study, we aimed to clarify the role of SIRT3 in osteogenic differentiation and the possible mechanisms, using mouse pre-osteoblastic MC3T3-E1 cells. Expression of SIRT3 was substantially increased in differentiated MC3T3-E1 cells. Knock down of SIRT3 significantly decreased alkaline phosphatase (ALP) staining, and mRNA expression of runt-related transcription factor 2 (Runx2) and collagen type I ɑ 1 (Col1ɑ1), and osteocalcin in differentiated MC3T3-E1 cells. Overexpression of wild type but not mutant SIRT3 could reverse SIRT3 knockdown-resulted decrease of ALP staining. Complex I, II, III, IV, and V activities, oxygen consumption and mitochondrial membrane potential were significantly decreased by SIRT3 knockdown. Moreover, SIRT3 knockdown reduced mitochondrial density, increased mitochondrial size and decreased the expression of NRF1 and TFAM. Knock down of SIRT3 decreased mRNA and protein expression of SOD2 and increased ROS level. Overexpression of SOD2 significantly suppressed SIRT3 knockdown-induced decrease of mitochondrial function and osteogenic differentiation. SIRT3 knockdown resulted in a significant decrease of PGC-1ɑ protein expression but not mRNA expression. Overexpression of wild type but not mutant SIRT3 could reverse SIRT3 knockdown-resulted decrease of PGC-1ɑ protein expression. Moreover, we detected a direct interaction between SIRT3 and PGC-1ɑ and SIRT3 knockdown reduced SIRT3 and PGC-1ɑ interaction, resulting in a reduction of PGC-1ɑ protein stability and PGC-1ɑ-binding in the promoters of SOD2. Overexpression of PGC-1ɑ blocked SIRT3 knockdown-induced decrease of SOD2 expression, increase of ROS level, and decrease of mitochondrial function and biogenesis, leading to improvement of osteogenesis. Overall, the data provide a better understanding of the role of SIRT3 in osteogenic differentiation.

Characteristics of expression and regulation of sirtuins in chicken (Gallus gallus).

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent protein deacetylases that are linked to post-translational regulation of many metabolic processes. There are few reports available for chicken sirtuins (designated cSIRT1-cSIRT7), whose expression and regulation in the liver have yet to be explored. In the present study, we characterized the expression and regulation of sirtuin family members in chicken liver. The results showed that the sirtuin family members in chicken share the same conserved functional SIR2 domains. All the sirtuin family members were expressed extensively in all tissues examined, and the expression levels of cSIRT1, cSIRT2, cSIRT4, cSIRT6, and cSIRT7 in the liver increased significantly with sexual maturity. However, all sirtuin family members were downregulated (P < 0.05) in chicken livers and cultured primary hepatocytes treated with 17β-estradiol. We concluded that the expression levels of some chicken sirtuin family members in the liver were upregulated with sexual maturation, but might not be regulated directly by estrogen. Whereas estrogen could be used as an inhibitor of all sirtuins, both in vivo and in vitro.

Histone Deacetylases with Antagonistic Roles in Saccharomyces cerevisiae Heterochromatin Formation.

As the only catalytic member of the Sir-protein gene-silencing complex, Sir2's catalytic activity is necessary for silencing. The only known role for Sir2's catalytic activity in Saccharomyces cerevisiae silencing is to deacetylate N-terminal tails of histones H3 and H4, creating high-affinity binding sites for the Sir-protein complex, resulting in association of Sir proteins across the silenced domain. This histone deacetylation model makes the simple prediction that preemptively removing Sir2's H3 and H4 acetyl substrates, by mutating these lysines to unacetylatable arginines, or removing the acetyl transferase responsible for their acetylation, should restore silencing in the Sir2 catalytic mutant. However, this was not the case. We conducted a genetic screen to explore what aspect of Sir2's catalytic activity has not been accounted for in silencing. Mutation of a nonsirtuin histone deacetylase, Rpd3, restored Sir-protein-based silencing in the absence of Sir2's catalytic activity. Moreover, this antagonism could be mediated by either the large or the small Rpd3-containing complex. Interestingly, this restoration of silencing appeared independent of any known histone H3 or H4 substrates of Rpd3 Investigation of Sir-protein association in the Rpd3 mutant revealed that the restoration of silencing was correlated with an increased association of Sir proteins at the silencers, suggesting that Rpd3 was an antagonist of Sir2's function in nucleation of Sir proteins to the silencer. Additionally, restoration of silencing by Rpd3 was dependent on another sirtuin family member, Hst3, indicating multiple antagonistic roles for deacetylases in S. cerevisiae silencing.

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice.

SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE−/− mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/− haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/−;ApoE−/− mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease.

P53-dependent SIRT6 expression protects Aβ42-induced DNA damage.

Alzheimer’s disease (AD) is the most common type of dementia and age-related neurodegenerative disease. Elucidating the cellular changes that occur during ageing is an important step towards understanding the pathogenesis and progression of neurodegenerative disorders. SIRT6 is a member of the mammalian sirtuin family of anti-aging genes. However, the relationship between SIRT6 and AD has not yet been elucidated. Here, we report that SIRT6 protein expression levels are reduced in the brains of both the 5XFAD AD mouse model and AD patients. Aβ42, a major component of senile plaques, decreases SIRT6 expression, and Aβ42-induced DNA damage is prevented by the overexpression of SIRT6 in HT22 mouse hippocampal neurons. Also, there is a strong negative correlation between Aβ42-induced DNA damage and p53 levels, a protein involved in DNA repair and apoptosis. In addition, upregulation of p53 protein by Nutlin-3 prevents SIRT6 reduction and DNA damage induced by Aβ42. Taken together, this study reveals that p53-dependent SIRT6 expression protects cells from Aβ42-induced DNA damage, making SIRT6 a promising new therapeutic target for the treatment of AD.

SIRT3 Acts as a Neuroprotective Agent in Rotenone-Induced Parkinson Cell Model.

SIRT3 is a member of Sirtuins family, which belongs to NAD(+) dependent class III histone deacetylases. Emerging evidence suggests that SIRT3 plays a pivotal role in regulating mitochondrial function. Mitochondrial dysfunction is a main pathogenesis of Parkinson's disease (PD). Here, we have investigated the protective effect of SIRT3 for PD cell model. The rotenone-induced human neuroblastoma SH-SY5Y cells damage was used as PD cell model. The lentiviral vectors were used to over-expression or knockdown SIRT3 expression. The cell viability was analyzed using MTT method. The apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured by flow cytometer. Superoxide dismutase (SOD) and glutathione (GSH) were detected by using automated microplate reader. The accumulation of α-synuclein was determined by immunofluorescence staining. SIRT3 knockdown significantly worsen rotenone-induced decline of cell viability (p<0.01) and enhanced cell apoptosis (p<0.01), exacerbated the decrease of SOD (p<0.05) and GSH (p<0.05), and augmented the accumulation of α-synuclein (p<0.05). While SIRT3 overexpression dramatically increased cell viability (p<0.01), and decreased cell apoptosis (p<0.01), prevented the accumulation of α-synuclein (p<0.05), suppressed the reducing of SOD (p<0.05) and GSH (p<0.01), decreased ROS generation (p<0.05), and alleviated MMP collapse (p<0.01) induced by rotenone. SIRT3 has neuroprotective effect in PD cell model and could be developed into a therapeutic agent for PD patients.

Lysine fatty acylation promotes lysosomal targeting of TNF-α.

Tumor necrosis factor-α (TNF-α) is a proinflammation cytokine secreted by various cells. Understanding its secretive pathway is important to understand the biological functions of TNF-α and diseases associated with TNF-α. TNF-α is one of the first proteins known be modified by lysine fatty acylation (e.g. myristoylation). We previously demonstrated that SIRT6, a member of the mammalian sirtuin family of enzymes, can remove the fatty acyl modification on TNF-α and promote its secretion. However, the mechanistic details about how lysine fatty acylation regulates TNF-α secretion have been unknown. Here we present experimental data supporting that lysine fatty acylation promotes lysosomal targeting of TNF-α. The result is an important first step toward understanding the biological functions of lysine fatty acylation.

Sirt1 deficiency protects cochlear cells and delays the early onset of age-related hearing loss in C57BL/6 mice

Hearing gradually declines with age in both animals and humans, and this condition is known as age-related hearing loss (AHL). Here, we investigated the effects of deficiency of Sirt1, a member of the mammalian sirtuin family, on age-related cochlear pathology and associated hearing loss in C57BL/6 mice, a mouse model of early-onset AHL. Sirt1 deficiency reduced age-related oxidative damage of cochlear hair cells and spiral ganglion neurons and delayed the early onset of AHL. In cultured mouse inner ear cell lines, Sirt1 knockdown increased cell viability under oxidative stress conditions, induced nuclear translocation of Foxo3a, and increased acetylation status of Foxo3a. This resulted in increased activity of the antioxidant enzyme catalase. In young wild-type mice, both Sirt1 and Foxo3a proteins resided in the cytoplasm of the supporting cells within the organ of Corti of the cochlea. Therefore, our findings suggest that SIRT1 promotes early-onset AHL through suppressing FOXO3a-mediated oxidative stress resistance in the cochlea of C57BL/6 mice.

SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy

Reduction in autophagy has been reported to contribute to the pathogenesis of cardiac hypertrophy. However, the molecular pathways leading to impaired autophagy at the presence of hypertrophic stimuli remain to be elucidated. The present study aimed to investigate the role of sirtuin 6 (SIRT6), a sirtuin family member, in regulating cardiomyocyte autophagy, and its implication in prevention of cardiac hypertrophy. Primary neonatal rat cardiomyocytes (NRCMs) or Sprague-Dawley (SD) rats were submitted to isoproterenol (ISO) treatment, and then the hypertrophic responses and changes in autophagy activity were measured. The influence of SIRT6 on autophagy was observed in cultured NRCMs with gain- and loss-of-function approaches to regulate SIRT6 expression, and further confirmed invivo by intramyocardial delivery of an adenovirus vector encoding SIRT6 cDNA. In addition, the involvement of SIRT6-mediated autophagy in attenuation of cardiomyocyte hypertrophy induced by ISO was determined basing on genetic or pharmaceutical disruption of autophagy, and the underlying mechanism was preliminarily explored. ISO-caused cardiac hypertrophy accompanying with a significant decrease in autophagy activity. SIRT6 overexpression enhanced autophagy in NRCMs and in rat hearts, whereas knockdown of SIRT6 by RNA interference led to suppression of cardiomyocyte autophagy. Furthermore, the protective effect of SIRT6 against ISO-stimulated hypertrophy was associated with induction of autophagy. SIRT6 promoted nuclear retention of forkhead box O3 transcription factor possibly via attenuating Aktsignaling, which was responsible for autophagy activation. Our findings revealedthat SIRT6 positively regulates autophagy in cardiomyocytes, which may help to ameliorate ISO-induced cardiac hypertrophy.

MMP-9, HIF-1 and SIRT1 in acute lung injury: a review

Matrix metallopeptidase 9 (MMP-9) is a group of enzymes that belong to the zine-metalloproteinases family involved in the pathophysiological process of various diseases, such as inflammation, angiogenesis and tumor invasion. Hypoxia-inducible factor-1(HIF-1) is a nucleoprotein with transcription activity, which consists of two different subunits, α and β. It plays an important role in the process of the formation of new blood vessels following ischemic necrosis and the process of hypoxia induced cell apoptosis. Silent information regulator2-related enzymes 1(SIRT1) is a NAD-dependent deacetylase sirtuin, which belongs to a member of the sirtuin family of proteins, also involved in many pathophysiologic processes, such as aging, cell death and tumorigenesis. This study aims to review the role of MMP-9, HIF-1 and SIRT1 in acute lung injury. Key words: Matrix metalloproteinase; Hypoxia-inducible factor-1; Silent information regulator2-related enzymes 1; Acute lung injury

SIRT1, 2, 3 protect mouse oocytes from postovulatory aging.

The quality of metaphase II oocytes will undergo a time-dependent deterioration following ovulation as the result of the oocyte aging process. In this study, we determined that the expression of sirtuin family members (SIRT1, 2, 3) was dramatically reduced in mouse oocytes aged in vivo or in vitro. Increased intracellular ROS was observed when SIRT1, 2, 3 activity was inhibited. Increased frequency of spindle defects and disturbed distribution of mitochondria were also observed in MII oocytes aged in vitro after treatment with Nicotinamide (NAM), indicating that inhibition of SIRT1, 2, 3 may accelerate postovulatory oocyte aging. Interestingly, when MII oocytes were exposed to caffeine, the decline of SIRT1, 2, 3 mRNA levels was delayed and the aging-associated defective phenotypes could be improved. The results suggest that the SIRT1, 2, 3 pathway may play a potential protective role against postovulatory oocyte aging by controlling ROS generation.

SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions

SIRT6 (sirtuin 6) is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis, and tumorigenesis. However, the role of SIRT6 deacetylase activity in its tumor-suppressor functions is not well understood. Here we report that SIRT6 binds to and deacetylates nuclear PKM2 (pyruvate kinase M2) at the lysine 433 residue. PKM2 is a glycolytic enzyme with nonmetabolic nuclear oncogenic functions. SIRT6-mediated deacetylation results in PKM2 nuclear export. We further have identified exportin 4 as the specific transporter mediating PKM2 nuclear export. As a result of SIRT6-mediated deacetylation, PKM2 nuclear protein kinase and transcriptional coactivator functions are abolished. Thus, SIRT6 suppresses PKM2 oncogenic functions, resulting in reduced cell proliferation, migration potential, and invasiveness. Furthermore, studies in mouse tumor models demonstrate that PKM2 deacetylation is integral to SIRT6-mediated tumor suppression and inhibition of metastasis. Additionally, reduced SIRT6 levels correlate with elevated nuclear acetylated PKM2 levels in increasing grades of hepatocellular carcinoma. These findings provide key insights into the pivotal role of deacetylase activity in SIRT6 tumor-suppressor functions.

Induction of Nuclear Enlargement and Senescence by Sirtuin Inhibitors in Glioblastoma Cells.

Sirtuin family members with lysine deacetylase activity are known to play an important role in anti-aging and longevity. Cellular senescence is one of the hallmarks of aging, and downregulation of sirtuin is reported to induce premature senescence. In this study, we investigated the effects of small-molecule sirtuin inhibitors on cellular senescence. Various small molecules such as tenovin-1 and EX527 were employed for direct sirtuin activity inhibition. U251, SNB-75, and U87MG glioblastoma cells treated with sirtuin inhibitors exhibited phenotypes with nuclear enlargement. Furthermore, treatment of rat primary astrocytes with tenovin-1 also increased the size of the nucleus. The activity of senescence-associated β-galactosidase, a marker of cellular senescence, was induced by tenovin-1 and EX527 treatment in U87MG glioblastoma cells. Consistent with the senescent phenotype, treatment with tenovin-1 increased p53 expression in U87MG cells. This study demonstrated the senescence-inducing effect of sirtuin inhibitors, which are potentially useful tools for senescence research.

Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro. The compound increased the acetylation level of eukaryotic translation initiation factor 5A (eIF5A), a physiological substrate of SIRT2, and reduced cell viability of human breast cancer cells accompanied with a decrease in c-Myc expression. These results suggest that the compound is cellular effective and has potential for development as a therapeutic agent against breast cancers by specific inhibition of SIRT2.

The complex role of SIRT6 in carcinogenesis.

SIRT6, a member of the mammalian sirtuins family, functions as a mono-ADP-ribosyl transferase and NAD(+)-dependent deacylase of both acetyl groups and long-chain fatty acyl groups. SIRT6 regulates diverse cellular functions such as transcription, genome stability, telomere integrity, DNA repair, inflammation and metabolic related diseases such as diabetes, obesity and cancer. In this review, we will discuss the implication of SIRT6 in the biology of cancer and the relevance to organism homeostasis and lifespan.