SIRT3

Gene Summary

Gene:SIRT3; sirtuin 3
Aliases: SIR2L3
Location:11p15.5
Summary:This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family. Two alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:NAD-dependent protein deacetylase sirtuin-3, mitochondrial
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Messenger RNA
  • HIF1A
  • Tumor Suppressor Proteins
  • Glucose
  • Superoxides
  • Mitochondria
  • Tumor Markers
  • RT-PCR
  • Acetylation
  • Sirtuins
  • Signal Transduction
  • Xenograft Models
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
  • Survival Rate
  • Sirtuin 3
  • Lymphatic Metastasis
  • Up-Regulation
  • Tamoxifen
  • p53 Protein
  • Genetic Variation
  • Adolescents
  • Chromosome 11
  • Unfolded Protein Response
  • Apoptosis
  • RTPCR
  • Knockout Mice
  • Cell Proliferation
  • Fibroblasts
  • Immunoenzyme Techniques
  • Lung Cancer
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • Oxidative Stress
  • Young Adult
  • Down-Regulation
  • Gene Expression
  • Cultured Cells
  • Breast Cancer
  • Glycolysis
  • p300-CBP Transcription Factors
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SIRT3 (cancer-related)

Wang JX, Yi Y, Li YW, et al.
Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection.
BMC Cancer. 2014; 14:297 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically.
METHODS: The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB).
RESULTS: IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis.
CONCLUSIONS: Down-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients.

Fan J, Shan C, Kang HB, et al.
Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.
Mol Cell. 2014; 53(4):534-48 [PubMed] Free Access to Full Article Related Publications
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal growth factor (EGF)-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1, and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important in promoting glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.

Papa L, Hahn M, Marsh EL, et al.
SOD2 to SOD1 switch in breast cancer.
J Biol Chem. 2014; 289(9):5412-6 [PubMed] Article available free on PMC after 28/02/2015 Related Publications
Cancer cells are characterized by elevated levels of reactive oxygen species, which are produced mainly by the mitochondria. The dismutase SOD2 localizes in the matrix and is a major antioxidant. The activity of SOD2 is regulated by the deacetylase SIRT3. Recent studies indicated that SIRT3 is decreased in 87% of breast cancers, implying that the activity of SOD2 is compromised. The resulting elevation in reactive oxygen species was shown to be essential for the metabolic reprograming toward glycolysis. Here, we show that SOD2 itself is down-regulated in breast cancer cell lines. Further, activation of oncogenes, such as Ras, promotes the rapid down-regulation of SOD2. Because in the absence of SOD2, superoxide levels are elevated in the matrix, we reasoned that mechanisms must exist to retain low levels of superoxide in other cellular compartments especially in the intermembrane space of the mitochondrial to avoid irreversible damage. The dismutase SOD1 also acts as an antioxidant, but it localizes to the cytoplasm and the intermembrane space of the mitochondria. We report here that loss of SOD2 correlates with the overexpression of SOD1. Further, we show that mitochondrial SOD1 is the main dismutase activity in breast cancer cells but not in non-transformed cells. In addition, we show that the SOD1 inhibitor LCS-1 leads to a drastic fragmentation and swelling of the matrix, suggesting that in the absence of SOD2, SOD1 is required to maintain the integrity of the organelle. We propose that by analogy to the cadherin switch during epithelial-mesenchymal transition, cancer cells also undergo a SOD switch during transformation.

Hoffmann G, Breitenbücher F, Schuler M, Ehrenhofer-Murray AE
A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer.
J Biol Chem. 2014; 289(8):5208-16 [PubMed] Article available free on PMC after 28/02/2015 Related Publications
Sirtuin 2 (SIRT2) is an NAD(+)-dependent protein deacetylase whose targets include histone H4 lysine 16, p53, and α-tubulin. Because deacetylation of p53 regulates its effect on apoptosis, pharmacological inhibition of SIRT2-dependent p53 deacetylation is of great therapeutic interest for the treatment of cancer. Here, we have identified two structurally related compounds, AEM1 and AEM2, which are selective inhibitors of SIRT2 (IC50 values of 18.5 and 3.8 μM, respectively), but show only weak effects on other sirtuins such as SIRT1, SIRT3, and yeast Sir2. Interestingly, both compounds sensitized non-small cell lung cancer cell lines toward the induction of apoptosis by the DNA-damaging agent etoposide. Importantly, this sensitization was dependent on the presence of functional p53, thus establishing a link between SIRT2 inhibition by these compounds and p53 activation. Further, treatment with AEM1 and AEM2 led to elevated levels of p53 acetylation and to increased expression of CDKN1A, which encodes the cell cycle regulator p21(WAF1), as well as the pro-apoptotic genes PUMA and NOXA, three transcriptional targets of p53. Altogether, our data suggest that inhibition of SIRT2 by these compounds causes increased activation of p53 by decreasing SIRT2-dependent p53 deacetylation. These compounds thus provide a good opportunity for lead optimization and drug development to target p53-proficient cancers.

Chen IC, Chiang WF, Chen PF, Chiang HC
STRESS-responsive deacetylase SIRT3 is up-regulated by areca nut extract-induced oxidative stress in human oral keratinocytes.
J Cell Biochem. 2014; 115(2):328-39 [PubMed] Related Publications
Areca chewing is an important environmental risk factor for development of oral premalignant lesions and cancer. Epidemiological evidence indicates that areca chewing is tightly linked to oral carcinogenesis. However, the pathogenetic impacts of areca nut extract (ANE) on normal human oral keratinocytes (HOKs) are unclear and possibly involve oxidative stress via redox imbalance. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that play an important role in regulating cellular reactive oxygen species (ROS) production. Recent studies have confirmed that ANE and other areca ingredients can induce ROS. In this study, we examined the role of SIRT3 in the regulation of ANE-induced ROS in HOK cells. We examined HOK cell viability following treatment with various ANE concentrations. ANE-induced cytotoxicity increased in a dose-dependent manner and was approximately 48% at a concentration of 50 μg/ml after 24 h. SIRT3 expression and enzyme activity were up-regulated in HOK cells by ANE-induced oxidative stress. Additionally, we identified that SIRT3 controls the enzymatic activity of mitochondrial proteins, such as forkhead box O3a (Foxo3a) transcription factor and antioxidant-encoding gene superoxide dismutase 2 (SOD2), by deacetylation in HOK cells. Moreover, SIRT3-mediated deacetylation and activation of Foxo3a promotes nuclear localization in vivo. These findings suggest that SIRT3 is an endogenous negative regulator in response to ANE-induced oxidative stress and demonstrate an essential role for redox balance in HOK cells.

Li H, Feng Z, Wu W, et al.
SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2.
Int J Oncol. 2013; 43(5):1420-30 [PubMed] Article available free on PMC after 28/02/2015 Related Publications
Lung cancer is the leading cause of death worldwide and associated with dismal prognoses. As a major mitochondrial deacetylase, SIRT3 regulates the activity of enzymes to coordinate global shifts in cellular metabolism and has important implications for tumor growth. Its role as a tumor suppressor or an oncogene in lung cancer is unclear, especially in non-small cell lung carcinoma (NSCLC). To identify the mechanism of SIRT3-interacting proteins, we performed a yeast two-hybrid screen using a human lung cDNA library. One of the positive clones encoded the full-length cDNA of the nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) gene and the interaction between SIRT3 and NMNAT2 was identified. The interaction on growth, proliferation, apoptosis of NSCLC cell lines, and energy metabolism related to SIRT3 were investigated. Screening from the library resulted in NMNAT2 gene. We found that NMNAT2 interacts with SIRT3 both in vitro and in vivo; SIRT3 binds to NMNAT2 deacetylating it. Downregulation of SIRT3 inhibited acetylation of NMNAT2 and NAD+ synthesis activity of the enzyme. Low expression of SIRT3 significantly inhibited mitotic entry, growth and proliferation of NSCLC cell lines and promoted apoptosis, which was related to energy metabolism involving in the interaction between SIRT3 and NMNAT2. Taken together, our results strongly suggest that the binding of SIRT3 with NMNAT2 is a novel regulator of cell proliferation and apoptosis in NSCLC cell lines, implicating the interaction between SIRT3 and NMNAT2, energy metabolism associated with SIRT3.

Tao R, Vassilopoulos A, Parisiadou L, et al.
Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis.
Antioxid Redox Signal. 2014; 20(10):1646-54 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
SIGNIFICANCE: It is a well-established scientific observation that mammalian cells contain fidelity or watchdog proteins that maintain the correct function of cellular organelles.
RECENT ADVANCES: Over the past several years, the Sirtuin deacetylase family protein Sirt3 has emerged as a mitochondrial fidelity protein that directs energy generation and regulates reactive oxygen species (ROS) scavenging proteins. Loss of function or genetic mutation of these fidelity proteins has been shown to create a cellular environment that is permissive for the development of cellular damage associated with processes such as aging and carcinogenesis.
CRITICAL ISSUES: Mitochondria are the primary organelles that direct oxidative metabolism for the production of ATP; however, this is also a significant source of ROS. Thus, it is reasonable to propose that mitochondria should contain proteins that would signal downstream target molecules and/or ROS scavenger enzymes to maintain mitochondrial and cellular homeostatic poise. It is also reasonable to hypothesize that the mitochondria contain fidelity proteins similar to those found in the nucleus and cytoplasm. We discuss a new role of Sirt3 in the direction of the primary superoxide scavenger protein, manganese superoxide dismutase (MnSOD), and how the acetylation or deacetylation of several specific lysines appears to direct MnSOD enzymatic dismutase activity.
FUTURE DIRECTIONS: Aberrant downstream regulation of MnSOD by Sirt3 may be a potential source of cellular damage that accumulates with aging to create a tumor-permissive phenotype. Future studies can explore the role of MnSOD in age-related illness using this new mechanism of enzymatic regulation.

Zhang L, Ren X, Cheng Y, et al.
Identification of Sirtuin 3, a mitochondrial protein deacetylase, as a new contributor to tamoxifen resistance in breast cancer cells.
Biochem Pharmacol. 2013; 86(6):726-33 [PubMed] Related Publications
The current study reports a previously unappreciated role of Sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, in altering sensitivity of breast cancer cells to tamoxifen (Tam), a commonly used anti-estrogen agent. We showed that SIRT3 was significantly up-regulated at both mRNA and protein levels in the Tam-resistance human breast cancer cell line MTR-3, which was derived from MCF-7 line by continuous selective culture in the presence of 1μM of Tam for two years. We further demonstrated that SIRT3 was rapidly up-regulated in the sensitive MCF-7 cells following exposure to Tam. Transfection of MCF-7 cells with a SIRT3 expression plasmid decreased cellular sensitivity to Tam and blocked the Tam-induced apoptosis. Furthermore, silencing of SIRT3 expression in MTR-3 cells sensitized the resistant cells to Tam and enhanced apoptotic cell death. MTR-3 cells with silencing of SIRT3 expression showed increases in the mitochondrial content of ERβ, ROS level and apoptosis. These results not only uncovered a new role for SIRT3 in cancer but also identified this mitochondrial protein deacetylase as a previously unrecognized factor that participates in regulation of Tam sensitivity in breast cancer cells. Thus, SIRT3 might be considered as a potential target for overcoming Tam resistance in treatment of breast cancer.

Chen IC, Chiang WF, Liu SY, et al.
Role of SIRT3 in the regulation of redox balance during oral carcinogenesis.
Mol Cancer. 2013; 12:68 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: Sirtuins (SIRT1-7) are a family of NAD-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; however, their role in oral cancer has been controversial. SIRT3 is localized in the mitochondria, where it deacetylates and activates several enzymes involved in cellular redox balance and defense against oxidative damage.
RESULTS: We found that compared with normal human oral keratinocytes (HOK), SIRT3 is highly expressed in oral squamous cell carcinoma (OSCC) cell lines, but the enzymatic deacetylation is significantly reduced. We also sequenced the entire coding region of SIRT3 and found the same mutation in 2 different OSCC cell lines. This point mutation is located in close proximity to the active site of deacetylase in the SIRT3 protein, and reduces the overall enzymatic efficiency of deacetylation. Furthermore, up-regulation of SIRT3 inhibited the cell growth of OSCCs and decreased the levels of basal reactive oxygen species (ROS) in both OSCC lines. To verify that the SIRT3 sequence variation was associated with oral carcinogenesis, we sequenced the SIRT3 gene from 21 OSCC patients, and 5 of the 21 patients (23.8%) carried the heterozygous missense mutation, p.Val208Ile. The heterozygous missense mutation in these patients was present in gremlin DNA isolated from both normal and tumor tissues.
CONCLUSIONS: Our findings provide a valuable insight into the potential role of SIRT3 in the development of oral squamous cell carcinoma, by showing that a non-synonymous point mutation in SIRT3 contributes to reduced catalytic activity of the protein and affects redox balance in OSCCs.

Aury-Landas J, Bougeard G, Castel H, et al.
Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours.
Eur J Hum Genet. 2013; 21(12):1369-76 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Germline alterations of the tumour suppressor TP53 gene are detected approximately in 25% of the families suggestive of Li-Fraumeni syndrome (LFS), characterised by a genetic predisposition to a wide tumour spectrum, including soft-tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumours, adrenocortical tumours, plexus choroid tumours, leukaemia and lung cancer. The aim of this study was to determine the contribution of germline copy number variations (CNVs) to LFS in families without detectable TP53 mutation. Using a custom-designed high-resolution array CGH, we evaluated the presence of rare germline CNVs in 64 patients fulfilling the Chompret criteria for LFS, but without any detectable TP53 alteration. In 15 unrelated patients, we detected 20 new CNVs absent in 600 controls. Remarkably, in four patients who had developed each brain tumour, the detected CNV overlap the KDM1A, MTA3, TRRAP or SIRT3 genes encoding p53 partners involved in histone methylation or acetylation. Focused analysis of SIRT3 showed that the CNV encompassing SIRT3 leads to SIRT3 overexpression, and that in vitro SIRT3 overexpression prevents apoptosis, increases G2/M and results in a hypermethylation of numerous genes. This study supports the causal role of germline alterations of genes involved in chromatin remodelling in genetic predisposition to cancer and, in particular, to brain tumours.

Lai CC, Lin PM, Lin SF, et al.
Altered expression of SIRT gene family in head and neck squamous cell carcinoma.
Tumour Biol. 2013; 34(3):1847-54 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) include a group of malignant neoplasms that arise from the upper aerodigestive tract and represent the seventh most common cause of cancer-related death. The overall 5-year survival rates have not significantly improved for decades in spite of the advances in the field of oncology and surgery, encouraging further research on factors that might modify disease prognosis. The silent information regulator (SIR) genes (Sirtuins) play key roles in cellular stress and are associated with aging-related diseases including cancer. Currently, seven human sirtuin (SIRT1-7) genes have been identified, but the roles of SIRT genes in HNSCC are still uncertain. Therefore, in this study, we used real-time quantitative reverse transcription-polymerase chain reaction to investigate the expressions of the seven SIRT genes in human HNSCC tissues to assess the changes in cancerous and noncancerous parts and the correlation with different tumor behaviors. Our results demonstrated that the expression levels of SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly downregulated in cancerous tissues compared with noncancerous tissues (all p<0.01). The expression levels of SIRT1, SIRT2, SIRT3, SIRT5, and SIRT7 showed downregulation in advanced stages in respect to early stages (p<0.05). These results indicate that the downregulation of SIRT genes expression may contribute to the development of cancer and trigger the neoplastic disease to more advanced stages. Our study indicates that SIRT genes expression could help in the diagnosis and represent a prognostic biomarker in HNSCC.

Zhang CZ, Liu L, Cai M, et al.
Low SIRT3 expression correlates with poor differentiation and unfavorable prognosis in primary hepatocellular carcinoma.
PLoS One. 2012; 7(12):e51703 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
SIRT3, a mitochondrial sirtuin belonging to nicotinamide adenine nucleotide (NAD) dependent deacetylases, is implicated in metabolism, longevity and carcinogenesis. SIRT3 expression and its significance in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we demonstrated that SIRT3 expression in HCC tissue was much lower than that in paracarcinoma tissue, at both mRNA and protein levels. The cutoff value for low SIRT3 expression in HCC was defined according to receiver operating characteristic curve (ROC) analysis. As disclosed by immunohistochemistry (IHC) results, low SIRT3 expression was present in 67.3% (167/248) of HCC cases. Furthermore, low expression of SIRT3 was significantly correlated to differentiation (P = 0.013), clinical stage (P = 0.005), serum AFP level (P<0.01), tumor multiplicity (P = 0.026) and relapse (P = 0.028). Moreover, Kaplan-Meier analysis indicated that low SIRT3 expression associated with unfavorable overall survival (P<0.01) and recurrence-free survival (P = 0.004). The prognostic impact of SIRT3 was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low SIRT3 expression was an independent poor prognostic marker for overall survival (Hazard Ratio (HR) 0.555, 95% confidence interval (95% CI) 0.344-0.897, P = 0.016). Collectively, we conclude that SIRT3 is decreased in HCC and is a novel unfavorable marker for prognosis of patients with this fatal disease.

Van Damme M, Crompot E, Meuleman N, et al.
HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance.
Epigenetics. 2012; 7(12):1403-12 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0-1-2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course.

Fiaschi T, Marini A, Giannoni E, et al.
Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay.
Cancer Res. 2012; 72(19):5130-40 [PubMed] Related Publications
Cancer-associated fibroblasts (CAF) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production, and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, prostate cancer cells, upon contact with CAFs, were reprogrammed toward aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia-inducible factor 1 (HIF1), which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability.

Villalba JM, Alcaín FJ
Sirtuin activators and inhibitors.
Biofactors. 2012 Sep-Oct; 38(5):349-59 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD(+) for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex(®) , SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.

Haigis MC, Deng CX, Finley LW, et al.
SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis.
Cancer Res. 2012; 72(10):2468-72 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Tumors exhibit metabolic reprogramming characterized by increased cellular reactive oxygen species (ROS) and the preferential use of glucose, which is known as the Warburg effect. However, the mechanisms by which these processes are linked remain largely elusive. Murine tumors lacking Sirt3 exhibit abnormally high levels of ROS that directly induce genomic instability and increase hypoxia-inducible factor 1α (HIF-1α) protein levels. The subsequent transcription of HIFα-dependent target genes results in cellular metabolic reprogramming and increased cellular glucose consumption. In addition, agents that scavenge ROS or reverse the Warburg effect prevent the transformation and malignant phenotype observed in cells lacking Sirt3. Thus, mice lacking Sirt3 provide a model that mechanistically connects aberrant ROS, the Warburg effect, and carcinogenesis.

D'Aquila P, Rose G, Panno ML, et al.
SIRT3 gene expression: a link between inherited mitochondrial DNA variants and oxidative stress.
Gene. 2012; 497(2):323-9 [PubMed] Related Publications
Signaling pathways between mitochondrial and nuclear genomes are activated to preserve cellular homeostasis, especially in the event of stress. Using cybrid cell lines, we investigated whether inherited mitochondrial DNA (mtDNA) variants modulate the expression profiles of mammalian sirtuins (SIRT1-7) under oxidative stress conditions. We found that the expression of the SIRT3 gene was down-regulated in cybrids harboring mtDNA of the J haplogroup, which correlated with mitochondrial function, resulting in a decline of NAD(+)/NADH and ATP levels. Overall, the data reported here highlight a link between SIRT3, mitochondrial DNA variability and mitochondrial functionality, three fundamental components of the cellular stress response.

Bayley JP, Devilee P
The Warburg effect in 2012.
Curr Opin Oncol. 2012; 24(1):62-7 [PubMed] Related Publications
PURPOSE OF REVIEW: A revival of interest in tumor metabolism is underway and here we discuss recent results with a focus on the central theme of the Warburg effect, aerobic glycolysis.
RECENT FINDINGS: The M2 tumor-specific isoform of pyruvate kinase has generated much interest, but it has now been reported that PKM2 is not specific to tumors. Despite this setback, the reciprocal regulation of PKM2, prolyl hydroxylase 3 and HIF-1 in a positive feedback loop shows that PKM2 is important to tumor metabolism. Hexokinase II was reported to be a crucial regulator of glycolysis in glioblastoma multiforme, and the importance of lactate dehydrogenase was underlined by evidence that a 'lactate-based dialog' exists between cancer cells and endothelial cells. A growing appreciation of the role of oncogenes and tumor suppressor genes in the Warburg effect was reflected in reports of the regulation of glutamine metabolism by p53, the role of c-Myc in the high glucose uptake of tumors, and the regulation of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) and ATP consumption by AKT. The sirtuins, SIRT3 and SIRT6, were also shown to play central roles in aerobic glycolysis and other aspects of tumor metabolism.
SUMMARY: The results discussed illustrate the growing integration of the previously distinct fields of molecular biological and metabolic cancer research and show that this synergy is beginning to yield a more complete and comprehensive understanding of the tumor cell.

Park SH, Ozden O, Jiang H, et al.
Sirt3, mitochondrial ROS, ageing, and carcinogenesis.
Int J Mol Sci. 2011; 12(9):6226-39 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS), are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor and this review will outline potential relationships between mitochondrial ROS/superoxide levels, aging, and cell phenotypes permissive for estrogen and progesterone receptor positive breast carcinogenesis.

Alhazzazi TY, Kamarajan P, Verdin E, Kapila YL
SIRT3 and cancer: tumor promoter or suppressor?
Biochim Biophys Acta. 2011; 1816(1):80-8 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Sirtuins (SIRT1-7), the mammalian homologues of the Sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. However, the role of several sirtuin family members, including SIRT1 and SIRT3, in cancer has been controversial. The aim of this review is to explore and discuss the seemingly dichotomous role of SIRT3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. This review will also discuss the potential role of SIRT3 as a novel therapeutic target to treat cancer.

Finley LW, Carracedo A, Lee J, et al.
SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
Cancer Cell. 2011; 19(3):416-28 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.

Schumacker PT
SIRT3 controls cancer metabolic reprogramming by regulating ROS and HIF.
Cancer Cell. 2011; 19(3):299-300 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
In this issue of Cancer Cell, Finley and coworkers report that the genetic loss of the deacetylase SIRT3 leads to metabolic reprogramming toward glycolysis. This shift is mediated by an increase in cellular reactive oxygen species (ROS) generation that amplifies HIF-α stabilization and HIF-dependent gene expression, thereby driving the tumor phenotype.

Bell EL, Emerling BM, Ricoult SJ, Guarente L
SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production.
Oncogene. 2011; 30(26):2986-96 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
It has become increasing clear that alterations in cellular metabolism have a key role in the generation and maintenance of cancer. Some of the metabolic changes can be attributed to the activation of oncogenes or loss of tumor suppressors. Here, we show that the mitochondrial sirtuin, SirT3, acts as a tumor suppressor via its ability to suppress reactive oxygen species (ROS) and regulate hypoxia inducible factor 1α (HIF-1α). Primary mouse embryo fibroblasts (MEFs) or tumor cell lines expressing SirT3 short-hairpin RNA exhibit a greater potential to proliferate, and augmented HIF-1α protein stabilization and transcriptional activity in hypoxic conditions. SirT3 knockdown increases tumorigenesis in xenograft models, and this is abolished by giving mice the anti-oxidant N-acetyl cysteine. Moreover, overexpression of SirT3 inhibits stabilization of HIF-1α protein in hypoxia and attenuates increases in HIF-1α transcriptional activity. Critically, overexpression of SirT3 decreases tumorigenesis in xenografts, even when induction of the sirtuin occurs after tumor initiation. These data suggest that SirT3 acts to suppress the growth of tumors, at least in part through its ability to suppress ROS and HIF-1α.

Li S, Banck M, Mujtaba S, et al.
p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase.
PLoS One. 2010; 5(5):e10486 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
A hallmark of p53 function is to regulate a transcriptional program in response to extracellular and intracellular stress that directs cell cycle arrest, apoptosis, and cellular senescence. Independent of the role of p53 in the nucleus, some of the anti-proliferative functions of p53 reside within the mitochondria [1]. p53 can arrest cell growth in response to mitochondrial p53 in an EJ bladder carcinoma cell environment that is naïve of p53 function until induced to express p53 [2]. TP53 can independently partition with endogenous nuclear and mitochondrial proteins consistent with the ability of p53 to enact senescence. In order to address the role of p53 in navigating cellular senescence through the mitochondria, we identified SirT3 to rescue EJ/p53 cells from induced p53-mediated growth arrest. Human SirT3 function appears coupled with p53 early during the initiation of p53 expression in the mitochondria by biochemical and cellular localization analysis. Our evidence suggests that SirT3 partially abrogates p53 activity to enact growth arrest and senescence. Additionally, we identified the chaperone protein BAG-2 in averting SirT3 targeting of p53 -mediated senescence. These studies identify a complex relationship between p53, SirT3, and chaperoning factor BAG-2 that may link the salvaging and quality assurance of the p53 protein for control of cellular fate independent of transcriptional activity.

Kim HS, Patel K, Muldoon-Jacobs K, et al.
SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.
Cancer Cell. 2010; 17(1):41-52 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.

Schumacker PT
A tumor suppressor SIRTainty.
Cancer Cell. 2010; 17(1):5-6 [PubMed] Related Publications
Sirtuin deacetylases are linked to longevity, aging, and stress responses. In this issue of Cancer Cell, Kim et al. show that SIRT3 functions as a tumor suppressor by enhancing the expression of mitochondrial MnSOD. Loss of SIRT3 leads to increased mitochondrial ROS, which then enhances cellular transformation and tumor growth.

Ashraf N, Zino S, Macintyre A, et al.
Altered sirtuin expression is associated with node-positive breast cancer.
Br J Cancer. 2006; 95(8):1056-61 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Sirtuins are genes implicated in cellular and organismal ageing. Consequently, they are speculated to be involved in diseases of ageing including cancer. Various cancers with widely differing prognosis have been shown to have differing and characteristic expression of these genes; however, the relationship between sirtuin expression and cancer progression is unclear. In order to correlate cancer progression and sirtuin expression, we have assessed sirtuin expression as a function of primary cell ageing and compared sirtuin expression in normal, 'nonmalignant' breast biopsies to breast cancer biopsies using real-time polymerase chain reaction (PCR). Levels of SIRT7 expression were significantly increased in breast cancer (P<0.0001). Increased levels of SIRT3 and SIRT7 transcription were also associated with node-positive breast cancer (P<0.05 and P<0.0001, respectively). This study has demonstrated differential sirtuin expression between nonmalignant and malignant breast tissue, with consequent diagnostic and therapeutic implications.

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