Gene Summary

Gene:SIRT3; sirtuin 3
Aliases: SIR2L3
Summary:SIRT3 encodes a member of the sirtuin family of class III histone deacetylases, homologs to the yeast Sir2 protein. The encoded protein is found exclusively in mitochondria, where it can eliminate reactive oxygen species, inhibit apoptosis, and prevent the formation of cancer cells. SIRT3 has far-reaching effects on nuclear gene expression, cancer, cardiovascular disease, neuroprotection, aging, and metabolic control. [provided by RefSeq, May 2019]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:NAD-dependent protein deacetylase sirtuin-3, mitochondrial
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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)

Xia C, He Z, Liang S, et al.
Metformin combined with nelfinavir induces SIRT3/mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice.
Eur J Pharmacol. 2019; 848:62-69 [PubMed] Related Publications
The molecular mechanisms underlying the antineoplastic properties of metformin combined with nelfinavir remain elusive. To explore this question, transmission electron microscopy (TEM) was used to observe the combinatorial effect of inducing autophagosome formation in human cervical cancer cells. Western blotting respectively assayed protein expression of LC3I, LC3II, Beclin-1, Autophagy-related protein 7 (Atg7), Autophagy-related protein 3 (Atg3), NAD-dependent deacetylase sirtuin-3 (SIRT3) and major histocompatibility complex class I chain-related gene A (MICA). Lactate dehydrogenase (LDH) cytotoxicity assay evaluated natural killer (NK) cell cytotoxicity in the presence of metformin and nelfinavir in combination or each drug alone. Using tumor xenografts in a nude mouse model, antitumor efficacy of the drug combination was assessed. We found that the drug combination could induce autophagosome formation in human cervical cancer cells. The biomarker proteins of autophagy, including Beclin-1, Atg7 and Atg3, decreased, but the ratios of LC3I/II increased. We also found that this drug combination sensitizes human cervical cancer cells to NK cell-mediated lysis by increasing the protein of SIRT3 and MICA. Moreover, this drug combination markedly induced autophagy of SiHa xenografts in nude mice. Therefore, it can be concluded that metformin, in combination with nelfinavir, can induce SIRT3/mROS-dependent autophagy and sensitize NK cell-mediated lysis in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings have revealed the detailed molecular mechanisms underlying the antitumor effects of metformin in combination with nelfinavir in cervical cancer.

Wang G, Wang JJ, Wang YZ, et al.
Myricetin nanoliposomes induced SIRT3-mediated glycolytic metabolism leading to glioblastoma cell death.
Artif Cells Nanomed Biotechnol. 2018; 46(sup3):S180-S191 [PubMed] Related Publications
As the most aggressive and malignant glioma, glioblastoma multiforme (GBM) abnormally expresses genes that mediate glycolytic metabolism and tumour cell growth. In this study, we investigated myricetin incorporated nanoliposomes and ascertained their prospect in effectively treating cancer via the employment of the GBM cell line DBTRG-05MG. Notably, the myricetin nanoliposomes (MYR-NLs) displayed potent inhibition of proliferation and significantly regulated the levels of proteins related to both glycolytic metabolism and cell survival. Most importantly, SIRT3 and phosphorylated p53 were also down-regulated by MYR-NLs, indicating that the MYR-NLs inhibited GBM cell growth through the SIRT3/p53-mediated PI3K/Akt-ERK and mitochondrial pathways. Our findings thus provide rational evidence that liposomal myricetin targeted at alternative cell death pathways may be a useful adjuvant therapy in glioblastoma treatment.

Huang S, Guo H, Cao Y, Xiong J
MiR-708-5p inhibits the progression of pancreatic ductal adenocarcinoma by targeting Sirt3.
Pathol Res Pract. 2019; 215(4):794-800 [PubMed] Related Publications
Numbers of studies have indicated that miRNA-708 plays an important role in many types of cancer. However, the role of miRNA-708 in pancreatic ductal adenocarcinoma (PDAC) has yet to be fully elucidated. The present study aimed to investigate the role of miRNA-708-5p in the proliferation, invasion and metastasis of PDAC in vitro, as well as the underlying mechanism. We found that miRNA-708-5p was upregulated in PDAC tissues and cell lines, and high miRNA-708 expression indicated poor prognosis in PDAC patients. Besides, the CCK-8 assay, colony formation assay and transwell assay results suggested that miRNA-708-5p overexpression enhanced the ability of proliferation, invasion and migration in PDAC cell lines. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and luciferase reporter assay demonstrated that SIRT3 was a direct target of miRNA-708-5p. Furthermore, a series of rescue experiments manifested that SIRT3 was involved in the oncogenic function of miRNA-708-5p in PDAC cells. Taken together, our study established a novel miRNA-708-5p/SIRT3 axis in the progression of pancreatic cancer and provided insight for pancreatic cancer treatment.

Zhou J, Shi M, Li M, et al.
Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis.
Cell Stress Chaperones. 2019; 24(2):369-383 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Sirtuin 3 (Sirt3)-modified mitochondrial fission participates in the progression of several types of cancers. However, its role in tongue cancer requires investigation. The aim of our study is to determine whether Sirt3 knockdown regulates the viability of tongue cancer cells via modulating mitochondrial fission. Two types of tongue cancer cells were used in the present study, and siRNA was transfected into the cells to suppress Sirt3 expression. Mitochondrial function and cell apoptosis were determined via immunofluorescence, Western blotting, ELISA, and qPCR assays. A pathway blocker was applied to verify the role of the JNK-Fis1 signaling pathway in regulation of mitochondrial fission. The present study showed that loss of Sirt3 promoted tongue cancer cell death in a manner dependent on mitochondrial apoptosis. Mitochondrial oxidative stress, energy metabolism disorder, mitochondrial cyt-c liberation, and mitochondrial apoptosis activation were observed after Sirt3 silencing. Furthermore, we demonstrated that Sirt3 knockdown activated mitochondrial stress via triggering Fis1-related mitochondrial fission and that inhibition of Fis1-related mitochondrial fission abrogated the pro-apoptotic effect of Sirt3 knockdown on tongue cancer cells. To this end, we found that Sirt3 modulated Fis1 expression via the c-Jun N-terminal kinases (JNK) signaling pathway and that blockade of the JNK pathway attenuated mitochondrial stress and repressed apoptosis in Sirt3 knockdown cells. Altogether, our results identified a tumor-suppressive role for Sirt3 deficiency in tongue cancer via activation of the JNK-Fis1 axis and subsequent initiation of fatal mitochondrial fission. Given these findings, strategies to repress Sirt3 activity and enhance the JNK-Fis1-mitochondrial fission cascade have clinical benefits for patients with tongue cancer.

Xu WY, Hu QS, Qin Y, et al.
Zinc finger E-box-binding homeobox 1 mediates aerobic glycolysis
World J Gastroenterol. 2018; 24(43):4893-4905 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
AIM: To uncover the roles of tumor-promoting gene
METHODS: Endogenous zinc finger E-box binding homeobox-1 (ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1 (MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3 (SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatin-immunoprecipitation assays.
RESULTS: ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1.
CONCLUSION: ZEB1 silenced SIRT3 expression

Bergaggio E, Riganti C, Garaffo G, et al.
IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies.
Blood. 2019; 133(2):156-167 [PubMed] Related Publications
Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (

Wei Z, Song J, Wang G, et al.
Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis.
Nat Commun. 2018; 9(1):4468 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The conversion of serine and glycine that is accomplished by serine hydroxymethyltransferase 2 (SHMT2) in mitochondria is significantly upregulated in various cancers to support cancer cell proliferation. In this study, we observed that SHMT2 is acetylated at K95 in colorectal cancer (CRC) cells. SIRT3, the major deacetylase in mitochondria, is responsible for SHMT2 deacetylation. SHMT2-K95-Ac disrupts its functional tetramer structure and inhibits its enzymatic activity. SHMT2-K95-Ac also promotes its degradation via the K63-ubiquitin-lysosome pathway in a glucose-dependent manner. TRIM21 acts as an E3 ubiquitin ligase for SHMT2. SHMT2-K95-Ac decreases CRC cell proliferation and tumor growth in vivo through attenuation of serine consumption and reduction in NADPH levels. Finally, SHMT2-K95-Ac is significantly decreased in human CRC samples and is inversely associated with increased SIRT3 expression, which is correlated with poorer postoperative overall survival. Our study reveals the unknown mechanism of SHMT2 regulation by acetylation which is involved in colorectal carcinogenesis.

Nie ZJ, Zhang YG, Chang YH, et al.
Exendin-4 inhibits glioma cell migration, invasion and epithelial-to-mesenchymal transition through GLP-1R/sirt3 pathway.
Biomed Pharmacother. 2018; 106:1364-1369 [PubMed] Related Publications
GLP-1 analogue exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist which shares 53% sequence with GLP-1, plays an essential role in human tumors. However, the function and mechanisms underlying the effects of exendin-4 on glioma cell migration, invasion and epithelial-to-mesenchymal transition are still obscure. Firstly, we demonstrated that GLP-1R was expressed in all glioma cell lines including U87, U251, U373 and A172. Exendin-4 treatment inhibited glioma cell survival, proliferation, migration and invasion. Also, exendin-4 inhibited epithelial-to-mesenchymal transition through positively regulating the expression of E-cadherin (epithelial marker), and negatively regulating the level of Vimentin (mesenchymal marker). Interestingly, we next demonstrated that exendin-4 elevated sirt3 expression dependent on the high level of GLP-1R in U87 and 251 cells. Finally, we confirmed that depletion the level of GLP-1R or sirt3 both reversed the inhibitory action of exendin-4 on glioma cell migration and invasion. These findings demonstrate that exendin-4 treatment suppressed the migration and invasion of glioma cells through GLP-1R/sirt3 pathway and exendin-4 plays an inhibitory effect on glioblastoma cell migration and invasion.

Wang L, Yu Z, Ren S, et al.
Metabolic reprogramming in colon cancer reversed by DHTS through regulating PTEN/AKT/HIF1α mediated signal pathway.
Biochim Biophys Acta Gen Subj. 2018; 1862(10):2281-2292 [PubMed] Related Publications
BACKGROUND: Metabolic reprogramming and hypoxia contribute to the resistance of conventional chemotherapeutic drugs in kinds of cancers. In this study, we investigated the effect of dihydrotanshinone I (DHTS) on reversing dysregulated metabolism of glucose and fatty acid in colon cancer and elucidated its mechanism of action.
METHODS: Cell viability was determined by MTT assay. Oxidative phosphorylation, glycolysis, and mitochondrial fuel oxidation were assessed by Mito stress test, glycolysis stress test, and mito fuel flex test, respectively. Anti-cancer activity of DHTS in vivo was evaluated in Colon cancer xenograft. Hexokinase activity and free fatty acid (FFA) content were assessed using respective Commercial kits. Gene expression patterns were determined by performing DNA microarray analysis and real-time PCR. Protein expression was assessed using immunoblotting and immunohistochemistry.
RESULTS: DHTS showed similar cytotoxicity against colon cancer cells under hypoxia and normoxia. DHTS decreased the efficiency of glucose and FA as mitochondrial fuels in HCT116 cells, which efficiently reversed by VO-OHpic trihydrate. DHTS reduced hexokinase activity and free fatty acid (FFA) content in tumor tissue of xenograft model of colon cancer. Gene expression patterns in metabolic pathways were dramatically differential between model and treatment group. Increases in PTEN and a substantial decrease in the expression of SIRT3, HIF1α, p-AKT, HKII, p-MTOR, RHEB, and p-ACC were detected.
CONCLUSIONS: DHTS reversed metabolic reprogramming in colon cancer through PTEN/AKT/HIF1α-mediated signal pathway.
GENERAL SIGNIFICANCE: The study is the first to report the reverse of metabolic reprogramming by DHTS in colon cancer. Meantime, SIRT3/PTEN/AKT/HIF1α mediated signal pathway plays a critical role during this process.

Li B, Chen X, Yang W, et al.
Single-walled carbon nanohorn aggregates promotes mitochondrial dysfunction-induced apoptosis in hepatoblastoma cells by targeting SIRT3.
Int J Oncol. 2018; 53(3):1129-1137 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Single-walled carbon nanohorns (SWNHs) can accumulate in a variety of cell types or tissues and exert biological effects, which have been demonstrated to induce apoptosis in hepatoblastoma cells. However, the role and molecular mechanisms of SWNHs remain unclear. The mitochondrion is an important subcellular structure and may contribute to apoptosis that is induced by SWNHs in hepatoblastoma cells. To address this question, the mitochondrial function of HepG2 or L02 cells that were treated with SWNHs was examined. The results indicated that SWNHs were able to decrease the mitochondrial membrane potential and suppress the activity of the Na+/K+-ATPase. Secondly, HepG2 cells and L02 cells were treated with SWNHs in vivo and in vitro. The expression of mitochondrial-associated proteins [acyl-CoA synthetase short chain family member 1, Bax, cytochrome C (CYT-C), sodium channel epithelial 1α subunit, sirtuin 3 (SIRT3) and voltage-dependent anion channel 1] was analyzed by western blotting and immunohistochemical staining. The results revealed that SWNH treatment was able to alter the expression of multiple mitochondrial apoptotic pathway-associated proteins in HepG2 cells. SWNH treatment was able upregulate the expression of SIRT3, CYT-C and VDAC1 and downregulate the expression of AceCS2, but it had a more stable effect on SIRT3. However, similar findings were not observed in L02 cells. Therefore, the data from the present study indicated that SWNHs might be used as a safe anticancer agent, where it is able to trigger mitochondrial dysfunction-induced apoptosis by upregulating SIRT3 expression in HepG2 cells.

Wang S, Li J, Xie J, et al.
Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway.
Oncogene. 2018; 37(30):4164-4180 [PubMed] Related Publications
Although PD-L1 has been shown to play a well-characterized role in inhibiting antitumor immunity via engagement of its receptor PD-1 in T lymphocytes, little is known about the tumor cell-intrinsic function of PD-L1 and its association with prognosis. Here, we investigate this issue and dissect the molecular mechanisms underlying the role of PD-L1 in glucose metabolism, proliferation, migration, and invasion in human cervical cancer cells. As a result, we found that PD-L1 overexpression in cervical cancer cells increases glucose metabolism and metastasis-related behaviors. Mechanistically, PD-L1 bound directly to integrin β4 (ITGB4), activating the AKT/GSK3β signaling pathway and consequently inducing the expression of the transcriptional repressor SNAI1. SNAIL in turn influenced the expression of genes involved in the epithelial-to-mesenchymal transition and regulated glucose metabolism by inhibiting SIRT3 promoter activity. High expression of PD-L1 and ITGB4 in human cervical carcinomas was significantly associated with lymph node metastasis and poor prognosis. Finally,

Grande IPP, Amorim PVGH, Freire ACTB, et al.
Differential gene expression of sirtuins between somatotropinomas and nonfunctioning pituitary adenomas.
Pituitary. 2018; 21(4):355-361 [PubMed] Related Publications
Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.

He XX, Huang CK, Xie BS
Autophagy inhibition enhanced 5‑FU‑induced cell death in human gastric carcinoma BGC‑823 cells.
Mol Med Rep. 2018; 17(5):6768-6776 [PubMed] Related Publications
The exact molecular mechanism of 5-fluorouracil (5-FU) in human gastric cancer cells remains to be elucidated. Cultured BGC‑823 human gastric carcinoma and AGS cell lines were treated with 5‑FU. Autophagosome formation was investigated through multiple approaches, including the quantification of green fluorescent protein‑microtubule‑associated protein 1A/1B‑light chain 3 (LC3) puncta, LC3 conversion and electron microscopy observations. Additionally, autophagy was inhibited using 3‑methyladenine (3‑MA) and beclin‑1 ablation, to determine its role in 5‑FU‑mediated cell death. In addition, the present study assessed alterations in sirtuin expression following 5‑FU treatment with reverse transcription‑quantitative polymerase chain reaction. 5‑FU treatment induced apoptosis and inhibited proliferation in BGC‑823 and AGS gastric cancer cells. It is of note that the 5‑FU treatment only promoted autophagy in BGC‑823 cells. Additionally, inhibition of autophagy by either 3‑MA or beclin‑1 ablation increased 5‑FU‑induced cell death in BGC‑823 cells. The present study quantified changes in sirtuin (SIRT1, SIRT3, SIRT5, and SIRT6) expression following 5‑FU treatment and using a specific inhibitor, sirtinol, the present study investigated their involvement in 5‑FU‑mediated autophagy. Autophagy inhibition through manipulation of sirtuin proteins may increase the therapeutic efficacy of the 5‑FU chemotherapeutic drug against gastric carcinoma.

Liu Z, Li L, Xue B
Effect of ganoderic acid D on colon cancer Warburg effect: Role of SIRT3/cyclophilin D.
Eur J Pharmacol. 2018; 824:72-77 [PubMed] Related Publications
Ganoderic acid D (GAD) is a highly oxygenated tetracyclic triterpenoid. This study aims to assess the effects of GAD on the energy metabolism of colon cancer through the regulation of SIRT3 expression and whether this effect is related to acetylated cyclophilin D. The results demonstrated that GAD inhibits the energy reprogramming of colon cancer cells including glucose uptake, lactate production, pyruvate and acetyl-coenzyme production in colon cancer cells. Meanwhile, GAD upregulated the protein expression of SIRT3. Furthermore, the interruption of SIRT3 expression significantly reversed all the effects of SIRT3 on the energy reprogramming of colon cancer. In addition, GAD induced the deacetylated cyclophilin D (CypD) by SIRT3, whereas SIRT3-shRNA inhibited its combining effect on CypD. The energy reprogramming effects of GAD on colon cancer seem to be mediated by SIRT3 upregulation via acetylated CypD inhibition.

Comelli M, Pretis I, Buso A, Mavelli I
Mitochondrial energy metabolism and signalling in human glioblastoma cell lines with different PTEN gene status.
J Bioenerg Biomembr. 2018; 50(1):33-52 [PubMed] Related Publications
Glioblastomas epidemiology and aggressiveness demand for a well characterization of biochemical mechanisms of the cells. The discovery of oxidative tumours related to chemoresistance is changing the prevalent view of dysfunctional mitochondria in cancer cells. Thus, glioblastomas metabolism is now an area of intense research, wherein was documented a high heterogeneity in energy metabolism and in particular in mitochondrial OxPhos. We report results gained by investigating mitochondrial OxPhos and bioenergetics, in a model of three human glioblastoma cell lines characterized by a different PTEN gene status. Functional data are analysed in relation to the expression levels of some main transcription factors and signalling proteins, which can be involved in the regulation of mitochondrial biogenesis and activity. Collectively, our observations indicate for the three cell lines a similar bioenergetic phenotype maintaining a certain degree of mitochondrial oxidative activity, with some difference for PTEN-wild type SF767 cells respect to PTEN-deleted A172 and U87MG characterized by a loss-of-function point mutation of PTEN. SF767 has lower ATP content and higher ADP/ATP ratio, higher AMPK activating-phosphorylation evoking energy impairment, higher OxPhos complexes and PGC1α-Sirt3-p53 protein abundance, in line with a higher respiration. Finally, SF767 shows a similar mitochondrial energy supply, but higher non-phosphorylating respiration linked to dissipation of protonmotive force. Intriguingly, it is now widely accepted that a regulated mitochondrial proton leak attenuate ROS generation and in tumours may be at the base of pro-survival advantage and chemoresistance.

Doherty A, Kernogitski Y, Kulminski AM, Pedro de Magalhães J
Identification of polymorphisms in cancer patients that differentially affect survival with age.
Aging (Albany NY). 2017; 9(10):2117-2136 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The World Health Organization predicts that the proportion of the world's population over 60 will almost double from 12% to 22% between 2015 and 2050. Ageing is the biggest risk factor for cancer, which is a leading cause of deaths worldwide. Unfortunately, research describing how genetic variants affect cancer progression commonly neglects to account for the ageing process. Herein is the first systematic analysis that combines a large longitudinal data set with a targeted candidate gene approach to examine the effect of genetic variation on survival as a function of age in cancer patients. Survival was significantly decreased in individuals with heterozygote or rare homozygote (i.e. variant) genotypes compared to those with a common homozygote genotype (i.e. wild type) for two single nucleotide polymorphisms (rs11574358 and rs4147918), one gene (

Zhang YK, Qu YY, Lin Y, et al.
Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients.
Nat Commun. 2017; 8(1):464 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The oncogenic mechanisms of overnutrition, a confirmed independent cancer risk factor, remain poorly understood. Herein, we report that enoyl-CoA hydratase-1 (ECHS1), the enzyme involved in the oxidation of fatty acids (FAs) and branched-chain amino acids (BCAAs), senses nutrients and promotes mTOR activation and apoptotic resistance. Nutrients-promoted acetylation of lys

Huang S, Chen X, Zheng J, et al.
Low SIRT3 expression contributes to tumor progression, development and poor prognosis in human pancreatic carcinoma.
Pathol Res Pract. 2017; 213(11):1419-1423 [PubMed] Related Publications
SIRT3, an important mitochondrial protein, may act as either an oncogene or tumor suppressor depending on the tumor-type. The aim of this study was to investigate the expression of SIRT3 in pancreatic carcinoma (PC) and its clinical association in PC patients. Immunohistochemistry was adopted to investigate the expression of SIRT3 in cancer and corrresponding adjacent non-cancer tissues across 79 patients with PC. The log-rank test and Cox hazard model were used to estimate the relationship between SIRT3 expression and prognosis. The staining results revealed that SIRT3 negative expression was more common in cancer tissues than in adjacent non-cancer tissues (P<0.001). Chi-square tests indicated that the expression of SIRT3 correlated with T status (p<0.001) and tumor stage (p=0.013). Kaplan-Meier analysis showed that negative SIRT3 expression is linked to a poor prognosis in PC patients. Multivariate analysis identified SIRT3 expression as an independent predictor for PC outcome both in the whole cohort and several subgroups of PC patients. Our results indicate that down-regulated SIRT3 may contribute to tumor progression and gloomy prognosis in PC patients and may sever as a novel prognostic marker.

Ren T, Zhang H, Wang J, et al.
MCU-dependent mitochondrial Ca
Oncogene. 2017; 36(42):5897-5909 [PubMed] Related Publications
Mitochondrial Ca

Cheng Y, Dai C, Zhang J
SIRT3-SOD2-ROS pathway is involved in linalool-induced glioma cell apoptotic death.
Acta Biochim Pol. 2017; 64(2):343-350 [PubMed] Related Publications
Glioma is the most prevalent type of adult primary brain tumor and chemotherapy of glioma was limited by drug-resistance. Linalool is an acyclic monoterpene alcohol possessing various pharmacological activities. The present study was conducted to evaluate the effect of linalool on glioma cell growth. The effect of linalool on cell viability in U87-MG cells was investigated and the results showed that linalool significantly reduced cell viability in a concentration- and time-dependent manner. In addition, exposure of the cells to linalool resulted in a concentration-dependent increase of TUNEL-stained cells, indicating the occurrence of apoptotic cell death. Linalool decreased mitochondrial oxygen consumption rate, increased the expression of Bax and Bak, reduced the expression of Bcl-2 and Bcl-xl, and increased the activities of caspase 3 and caspase 9, leading to increase of apoptosis. Linalool resulted in a concentration-dependent decrease of SOD activity but had no significant effect on mRNA and protein expression of SOD2. Moreover, linalool resulted in a significant increase of the expression of acetylated SOD2. The mRNA and protein expression of SIRT3 was significantly inhibited by linalool. Immunoblot analysis showed that there was an evident protein/protein interaction between SOD2 and SIRT3 under normal condition. Linalool treatment significantly decreased the interaction between SOD2 and SIRT3. Overexpression of SIRT3 significantly inhibited linalool-induced increase of mitochondrial ROS production and apoptotic cell death, and decrease of cell viability. In summary, the data demonstrated that linalool exhibited inhibitory effect on glioma cells through regulation of SIRT3-SOD2-ROS signaling.

Panza S, Santoro M, De Amicis F, et al.
Estradiol via estrogen receptor beta influences ROS levels through the transcriptional regulation of SIRT3 in human seminoma TCam-2 cells.
Tumour Biol. 2017; 39(5):1010428317701642 [PubMed] Related Publications
Human testis, gonocytes, and adult germ cells mainly express estrogen receptor beta, and estrogen receptor beta loss is associated with advanced tumor stage; however, the molecular mechanisms of estrogen receptor beta-protective effects are still to be defined. Herein, we provide evidence that in human seminoma TCam-2 cells, E2 through estrogen receptor beta upregulates the mitochondrial deacetylase sirtuin-3 at protein and messenger RNA levels. Specifically, E2 increases sirtuin-3 expression through a transcriptional mechanism due to the occupancy of sirtuin-3 promoter by estrogen receptor beta, together with the transcription factor Sp1 as evidenced by Chip reChIp assay. This complex binds to a GC cluster located between -128 bp/+1 bp and is fundamental for E2 effects, as demonstrated by Sp1 small interfering RNA studies. Beside, after 24 h, E2 stimulus significantly increased activities of superoxide dismutase and catalase to scavenge reactive oxygen species produced by 30 min of E2 stimulus. In summary, this article indicates a novel functional interplay between estrogen receptor beta and sirtuin-3 counteracting reactive oxygen species production in TCam-2 cells. Our findings thus show that an important tumor-suppressive pathway through estrogen receptor beta is target of E2, actually proposing a distinctive protecting action against seminoma. Future studies may lead to additional strategies for the current therapy of seminoma.

Liu Y, Liu YL, Cheng W, et al.
The expression of SIRT3 in primary hepatocellular carcinoma and the mechanism of its tumor suppressing effects.
Eur Rev Med Pharmacol Sci. 2017; 21(5):978-998 [PubMed] Related Publications
OBJECTIVE: To observe the SIRT 3 expression in primary hepatocellular carcinoma (HCC), and then establish the eukaryotic expression vector of SIRT3 to observe the proliferation and apoptosis of pZsGreen-c1-SIRT3 HepG2 cells. Furthermore, we explored the mechanism of SIRT3 in inhibiting HCC.
PATIENTS AND METHODS: Immunohistochemistry was used to detect the expression of SIRT3 in the tumor tissue and para-tumor tissue in 32 patients with HCC and the normal liver tissue in 10 patients. The mRNA of SIRT3 from the normal liver tissue was used as a template, reverse transcription-polymerase chain reaction (RT-PCR) was used to obtain the total sequence of SIRT3 gene, and then the gene was cloned and combined with vector pZsGreen-c1, liposome transfection technology was used to transfect the recombined plasmid into HepG2. The cells were divided into three groups: group A (HepG2 cells as a blank control group), group B (pZsGreen-c1 HepG2 cells as an experimental control group) and group C (pZsGreen-c1-SIRT3 HepG-2 cells as an experimental group). MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay was used to detect the growth and proliferation of cells in 3 groups; annexinV/PI double staining was used to detect the apoptotic rates of cells in 3 groups. Western blot was used to detect the protein expression of SIRT3, Fas, Bax and P53, and water-soluble tetrazolium salt (WST-1) was used to detect MnSOD content in 3 groups.
RESULTS: Immunohistochemistry results showed that SIRT3 in the tumor tissue sample was positive in 19 patients out of 32 HCC patients; however, there was no strong positive case, the positive rate of SIRT3 expression was 59.38% (19/32). SIRT3 in the para-tumor tissue was positive in 31 HCC patients, the positive rate was 96.88% (31/32), and 18 cases were strongly positive; SIRT3 in normal liver tissue was positive in all 10 cases, the positive rate was 100.0% (10/10), and 7 cases were strongly positive. The differences of SIRT3 positive rate and positive score in tumor tissue from para-tumor tissue and normal liver tissue were statistically significant (p<0.05). However, the differences between para-tumor tissue and normal liver tissue were not statistically significant (p>0.05). After pZsGreen-c1-SIRT3 transfection, MTT results showed that the OD values in 3 groups were increased with the time, showing time-dependent manner. At 48 h after culture, the OD values in-group C were significantly different from group A and B, and the inhibitory rates were statistically different (p<0.05). After 48 h, the OD values and inhibitory rates in-group C showed that the cells were obviously inhibited, and the inhibitory rates were increased with the time, showing time-dependent manner. Flow cytometry results showed that the cell numbers of early stage apoptosis and late stage apoptosis were significantly increased in group C, which was significantly higher than group A and B, the differences were statistically significant (p<0.01). Western blot results showed that expression levels of SIRT3, p53, Bax and Fas were not different between group A and B (p>0.05); SIRT3, p53, Bax and Fas in group C were significantly increased, which were statistically higher than group A and B (p<0.01). WST-1 results showed that MnSOD contents were not statistically different between group A and B (p>0.01). MnSOD content in-group C was significantly higher than the other groups, which were statistically significant (p<0.01).
CONCLUSIONS: SIRT3 shows low expression or deficiency in HCC tissue, indicating that SIRT3 expression can affect the occurrence and development of HCC. SIRT3 can inhibit the growth and proliferation of HepG2 cells and induce HepG2 cell apoptosis. The mechanism may be related to the up-regulation of MnSOD and p53, the up-regulation of Bax and Fas by MnSOD.

Zhang Y, Xu YY, Yao CB, et al.
Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone.
Autophagy. 2017; 13(3):538-553 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Dysregulation of hormone metabolism is implicated in human breast cancer. 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) catalyzes the conversion of estradiol (E2) to estrone (E1), and is associated with the pathogenesis and development of various cancers. Here we show that E1 upregulates HSD17B4 acetylation at lysine 669 (K669) and thereby promotes HSD17B4 degradation via chaperone-mediated autophagy (CMA), while a single mutation at K669 reverses the degradation and confers migratory and invasive properties to MCF7 cells upon E1 treatment. CREBBP and SIRT3 dynamically control K669 acetylation level of HSD17B4 in response to E1. More importantly, K669 acetylation is inversely correlated with HSD17B4 in human breast cancer tissues. Our study reveals a crosstalk between acetylation and CMA degradation in HSD17B4 regulation, and a critical role of the regulation in the malignant progression of breast cancer.

Shah AA, Ito A, Nakata A, Yoshida M
Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity.
Biol Pharm Bull. 2016; 39(10):1739-1742 [PubMed] Related Publications
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.

Lone MU, Baghel KS, Kanchan RK, et al.
Physical interaction of estrogen receptor with MnSOD: implication in mitochondrial O
Oncogene. 2017; 36(13):1829-1839 [PubMed] Related Publications
Augmented reactive oxygen species levels consequential to functional alteration of key mitochondrial attributes contribute to carcinogenesis, either directly via oxidative DNA damage infliction or indirectly via activation of oncogenic signaling cascades. We previously reported activation of a key oncogenic signaling cascade via mammalian target of rapamycin (mTOR) signaling complex-2 (mTORC2) owing to estrogen receptor (ER-α)-dependent augmentation of O

Bigagli E, De Filippo C, Castagnini C, et al.
DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up.
Cell Oncol (Dordr). 2016; 39(6):545-558 [PubMed] Related Publications
BACKGROUND: DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study.
METHODS: Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up.
RESULTS: DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p < 0.01). The expression of 65 genes was found to be significantly associated with prognosis (p < 0.01). Specifically, we found that up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, were strongly associated with a poor survival. Subsequent integrated analyses revealed that increased expression levels of the MMP9, BMP7, UBE2C, I-CAM, NOTCH3, NOTCH1, PTGES2, HMGB1 and ERBB3 genes were associated with copy number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-β and apoptosis signaling, were found to be most significantly affected.
CONCLUSIONS: Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging, be employed as new prognostic biomarkers for the prediction of clinical outcome in CRC patients.

Kumar A, Corey C, Scott I, et al.
Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53-Dependent Manner in Non-Small Cell Lung Cancer.
PLoS One. 2016; 11(8):e0160783 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Minnelide/Triptolide (TL) has recently emerged as a potent anticancer drug in non-small cell lung cancer (NSCLC). However, the precise mechanism of its action remains ambiguous. In this study, we elucidated the molecular basis for TL-induced cell death in context to p53 status. Cell death was attributed to dysfunction of mitochondrial bioenergetics in p53-deficient cells, which was characterized by decreased mitochondrial respiration, steady-state ATP level and membrane potential, but augmented reactive oxygen species (ROS). Increased ROS production resulted in oxidative stress in TL-treated cells. This was exhibited by elevated nuclear levels of a redox-sensitive transcriptional factor, NF-E2-related factor-2 (NRF2), along with diminished cellular glutathione (GSH) content. We further demonstrated that in the absence of p53, TL blunted the expression of mitochondrial SIRT3 triggering increased acetylation of NDUAF9 and succinate dehydrogenase, components of complexes I and II of the electron transport chain (ETC). TL-mediated hyperacetylation of complexes I and II proteins and these complexes displayed decreased enzymatic activities. We also provide the evidence that P53 regulate steady-state level of SIRT3 through Proteasome-Pathway. Finally, forced overexpression of Sirt3, but not deacetylase-deficient mutant of Sirt3 (H243Y), restored the deleterious effect of TL on p53-deficient cells by rescuing mitochondrial bioenergetics. On contrary, Sirt3 deficiency in the background of wild-type p53 triggered TL-induced mitochondrial impairment that echoed TL effect in p53-deficeint cells. These findings illustrate a novel mechanism by which TL exerts its potent effects on mitochondrial function and ultimately the viability of NSCLC tumor.

Torrens-Mas M, Pons DG, Sastre-Serra J, et al.
SIRT3 Silencing Sensitizes Breast Cancer Cells to Cytotoxic Treatments Through an Increment in ROS Production.
J Cell Biochem. 2017; 118(2):397-406 [PubMed] Related Publications
SIRT3, the major deacetylase in mitochondria, plays a crucial role modulating ROS production and scavenging by regulating key proteins implicated in mitochondrial turnover and in antioxidant defenses. Therefore, SIRT3 could confer resistance to chemotherapy-induced oxidative stress, leading to a lower ROS production and a higher cell survival. Our aim was to analyze whether SIRT3 silencing in breast cancer cells through a specific siRNA could increase oxidative stress and thus compromise the antioxidant response, resulting in a sensitization of the cells to cisplatin (CDDP) or tamoxifen (TAM). For this purpose, we studied cell viability, ROS production, apoptosis and autophagy in MCF-7 and T47D cell lines treated with these cytotoxic compounds, these either alone, or in combination with SIRT3 silencing. Moreover, protein levels regulated by SIRT3 were also examined and survival curves were analyzed to study the importance of SIRT3 expression for the overall survival of breast cancer patients. When SIRT3 was silenced and combined with cytotoxic treatments, cell viability was highly decreased, and was accompanied by a significant increase in ROS production. While TAM treatment increased autophagic cell death, CDDP significantly triggered apoptosis, whereas SIRT3 silencing produced an enhancement of these two action mechanisms. SIRT3 knockdown also affected PGC-1α and TFAM (mitochondrial biogenesis), and MnSOD and IDH

Tao NN, Zhou HZ, Tang H, et al.
Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway.
Oncotarget. 2016; 7(31):50117-50130 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
SIRT3, a class III histone deacetylase, has been implicated in various cancers as a novel therapeutic target. In hepatocellular carcinoma (HCC), we previously reported that SIRT3 induced cell apoptosis by regulating GSK-3β/Bax signaling pathway. Downregulation of SIRT3 in HCC cells facilitates tumor cell survival. In this study, we found that chemotherapeutic agents (doxorubicin, cisplatin and epirubicin) and sorafenib treatment downregulated SIRT3 mRNA and protein levels in three HCC cell lines. MTS assay found that SIRT3 overexpression sensitized liver cancer cells to chemotherapeutic agents and sorafenib in SMMC-7721, Huh-7 and PLC/PRF/5 cell lines. Moreover, SIRT3 overexpression promoted chemotherapeutic agents-induced or sorafenib-induced apoptosis as evidenced by flow cytometry, enhanced PARP cleavage and enhanced Caspase-9 cleavage in three HCC cells. In contrast, SIRT3 silencing increased drug resistance of HCC cells to chemotherapeutic agents. Mechanistic study found that SIRT3 downregulated the mRNA and protein levels of glutathione S-transferase pi 1 (GSTP1), which is a member of phase II detoxification enzymes families involved in metabolizing for chemotherapeutic agents. Moreover, SIRT3 decreased the amount of GSTP1 that was associated with JNK, which finally contributed the activation of JNK activity and activation of downstream target c-Jun and Bim. Importantly, GSTP1 overexpression or JNK inhibitor abolished SIRT3-induced apoptosis in HCC cells exposed to chemotherapeutic agents. Finally, there was a negative correlation between SIRT3 expression and GSTP1 expression in human HCC tissues. Together, our findings revealed SIRT3 could enhance the drug sensitivity of HCC cells to an array of chemotherapeutic agents. SIRT3 may serve as a potential target for improving the chemosensitivity of HCC patients.

Xiang XY, Kang JS, Yang XC, et al.
SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells.
Int J Oncol. 2016; 49(2):773-84 [PubMed] Related Publications
The Bcl-2 antiapoptotic proteins are important cancer therapy targets; however, their role in cancer cell metabolism remains unclear. We found that the BH3-only protein mimetic S1, a novel pan Bcl-2 inhibitor, simultaneously interrupted glucose metabolism and induced apoptosis in human SKOV3 ovarian cancer cells, which was related to the activation of SIRT3, a stress-responsive deacetylase. S1 interrupted the cellular glucose metabolism mainly through causing damage to mitochondrial respiration and inhibiting glycolysis. Moreover, S1 upregulated the gene and protein expression of SIRT3, and induced the translocation of SIRT3 from the nucleus to mitochondria. SIRT3 silencing reversed the effects of S1 on glucose metabolism and apoptosis through increasing the level of HK-II localized to the mitochondria, while a combination of the glycolysis inhibitor 2-DG and S1 intensified the cytotoxicity through further upregulation of SIRT3 expression. This study underscores an essential role of SIRT3 in the antitumor effect of Bcl-2 inhibitors in human ovarian cancer through regulating both metabolism and apoptosis. The manipulation of Bcl-2 inhibitors combined with the use of classic glycolysis inhibitors may be rational strategies to improve ovarian cancer therapy.

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