- Open Access
Sirtuins in metabolism, DNA repair and cancer
- Zhen Mei†1, 2,
- Xian Zhang†1, 2,
- Jiarong Yi1, 2,
- Junjie Huang1, 2,
- Jian He1, 2 and
- Yongguang Tao1, 2Email author
© The Author(s). 2016
- Received: 25 August 2016
- Accepted: 19 November 2016
- Published: 5 December 2016
The mammalian sirtuin family has attracted tremendous attention over the past few years as stress adaptors and post-translational modifier. They have involved in diverse cellular processes including DNA repair, energy metabolism, and tumorigenesis. Notably, genomic instability and metabolic reprogramming are two of characteristic hallmarks in cancer. In this review, we summarize current knowledge on the functions of sirtuins mainly regarding DNA repair and energy metabolism, and further discuss the implication of sirtuins in cancer specifically by regulating genome integrity and cancer-related metabolism.
- DNA damage
- Post-translation modification
The host cells are constantly subjected to oxidative, genotoxic and metabolic stress. The ratio of NAD+/NADH is correlated with stress resistance, oxidative metabolism and DNA repair . Sensing intracellular NAD+ changes, sirtuins are proposed to work as stress adaptors. Meanwhile, given their diverse enzymatic activities, they are described to play critical roles in regulating post-translational modifications (PTMs), among which acetylation is an important form. Sirtuins deacetylate a multitude of targets including histones, transcription factors, and metabolic enzymes. Taken together, sirtuins have been implicated in numerous cellular processes including stress response, DNA repair, energy metabolism, and tumorigenesis [8, 9].
Aberrant cellular metabolism in cancer cells characterized by elevated aerobic glycolysis and extensive glutaminolysis  is essential to fuel uncontrolled proliferation and malignant tumor growth. The Warburg effect, which describes that tumor cells preferentially use glucose for aerobic glycolysis in the presence of ample oxygen , has emerged as one of hallmarks of cancer. Even though originally thought to be energy insufficient, Warburg effect is now widely accepted to confer rapid proliferation and invasive properties to tumor cells [12–14]. In parallel, many cancer cells exhibits enhanced glutamine metabolism and cannot survive in the absence of glutamine . Recent studies have shown that a succession of well-established oncogenic cues, including Myc, Ras or mammalian target of rapamycin complex 1 (mTORC1) pathways play imperative roles in inducing glutaminolysis [16–18]. Besides metabolic reprogramming, deregulated DNA-repair pathways and subsequent genome instability appears to facilitate the acquisition of tumorigenic mutations propitious to tumor growth and cancer progression [19, 20].
Mounting evidence has shed light on that sirtuins play diverse parts in cancer . In this review, we summarize an overview and update on the function of sirtuins in metabolism and DNA repair, and further touch on their roles in cancer mainly by affecting genome integrity and cancer-associated metabolism.
SIRT1 is the most conserved mammalian NAD + −dependent protein deacetylase that has emerged as a regulator of glucose metabolism. As for gluconeogenesis, the role of SIRT1 is regarded as dual and intricate. In a short-term fasting phase, SIRT1 induces decreased hepatic glucose production by suppressing CRTC2 (CREB-regulated transcription coactivator 2), a key mediator of early phase gluconeogenesis . With the fasting phase prolonged, SIRT1 deacetylates and activates both the transcription factor FOXO1 (forkhead box protein O1) and its co-activator PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1 α) [22, 23], which reinforces the gluconeogenic transcriptional program. In respect to glycolysis, SIRT1 attenuates the transcription of glycolytic genes by directly deacetylating transcription factor HIF1α  and also inhibits glycolytic enzyme PGAM1 (phosphoglycerate mutase 1) through deactylation . SIRT1 is also implicated in glucose metabolism by functioning as an insulin sensitizer. Through transcriptionally repressing the uncoupling protein 2 (UCP2), SIRT1 positively modulates glucose-stimulated insulin secretion . Accumulating evidence suggests that SIRT1 and SIRT1 activators can prevent and reverse insulin resistance and diabetic complications, proven to be a promising therapeutic target in type 2 diabetes (T2D) [27–30].
Compared to SIRT1, SIRT2 is predominantly a cytoplasmic protein and pretty abundant in adipocytes. SIRT2 activates the rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) via deacetylation and enhances gluconeogenesis during times of glucose deprivation . Meanwhile recent studies have proposed that, in regard to insulin sensitivity, SIRT2 may act specific and opposing roles in different tissues .
SIRT3, SIRT4, and SIRT5
Primarily located in mitochondria, SIRT3, SIRT4, and SIRT5 sense and regulate the energy status in this organelle. Activating glutamate dehydrogenase (GDH), SIRT3 facilitates gluconeogenesis from amino acids . In addition, SIRT3 indirectly destabilizes transcription factor HIF1α and subsequently inhibits glycolysis and glucose oxidation . Intriguingly, recent studies have shown that SIRT3 levels in pancreatic islets are reduced in patients afflicted with type 2 diabetes  and SIRT3 overexpression in pancreatic β-cells promotes insulin secretion and abrogates endoplasmic reticulum (ER) stress that is connected to β-cell dysfunction and apoptosis .
SIRT4, initially reported as a unique ADP-ribosyltransferase, appears to blunt insulin secretion by reducing GDH activity . In line with this, the amino acid-stimulated insulin secretion is upregulated in SIRT4-deficient insulinoma cells . Besides GDH, a diverse range of SIRT4 targets are identified in the regulation of insulin secretion including ADP/ATP carrier proteins, insulin-degrading enzyme, ANT2 and ANT3 . Interestingly SIRT4 is characterized as a lipoamidase and diminishes pyruvate dehydrogenase complex (PDH) activity, an enzyme converting pyruvate to acetyl CoA and connecting glycolysis to the TCA cycle .
In contrast to other sirtuins, SIRT5 displays deacetylase and NAD + −dependent demalonylase and desuccinylase activities. SIRT5 facilitates glycolysis via demalonylating the glycolytic enzyme glyceraldehyde phosphate dehydrogenase (GAPDH) . And a recent study proposed that SIRT5 might be positively correlated with insulin sensitivity, the biological significance of which still remains to be confirmed .
There is growing appreciation that SIRT6 plays a critical role in glucose homeostasis. In the case of gluconeogenesis, SIRT6 indirectly suppresses PGC-1α leading to downregulation of hepatic glucose production . Similar to SIRT1, SIRT6 can also shut down the glycolytic flux by deacetylation of histone H3 lysine 9 (H3K9) in promoters of glycolytic genes and acting as a HIF1α corepressor . In this regard, one recent study revealed that the antiglycolytic activity of SIRT6 exerts beneficial impact against nasal polyp formation . Meanwhile, SIRT6 may positively mediate glucose-stimulated insulin secretion  and overexpression of it enhances insulin sensitivity in skeletal muscle and liver, emerging as an attractive therapeutic target for T2D.
SIRT1, SIRT3 and SIRT6, as discussed above, have all been identified to exert repressive effect on HIF-1 activity through different mechanisms. Likewise, it was reported that Sirt7 overexpression decreased HIF-1α and HIF-2α protein levels through a distinct mechanism independent of its deacetylase activity . Besides, Sirt7 knockout mice were resistant to glucose intolerance and insulin sensitivity is improved in Sirt7 knockout mice receiving a high-fat diet . All these findings revealed a novel role for SIRT7 in glucose metabolism.
In addition to its critical roles in glucose metabolism, SIRT1 is also convinced to regulate lipid homeostasis. During fasting, SIRT1 deacetylates and destabilizes sterol regulatory element binding protein 1 (SREBP1), a hepatic transcription factors for lipogenesis and cholesterol synthesis, which theoretically represses fatty acid and cholesterol synthesis . In agreement with this, a recent study points out an increase of de novo lipogenesis upon SIRT1 inhibition in human fetal hepatocytes . Moreover, the complex transcriptional program controlling adipogenesis is mainly coordinated by the nuclear receptor PPARγ. SIRT1 reduces the activity of PPARγ and suppresses adipogenesis in situation of nutrient depletion, subsequently engendering increased lipolysis and fat mobilization from WAT .
SIRT1 also occupies a special place in lipid metabolism via enhancing lipid oxidation. In support of this notion, activation of PPARα and its coactivator PGC1α by SIRT1 are presented in both liver and skeletal muscle, which stimulates the expression of β-oxidation related genes [50, 51]. Of note, AMPK, an energy sensor, is also involved in fatty acid oxidation in skeletal muscle and its interaction with SIRT1 is described as a reciprocal regulatory loop, in which AMPK upregulates SIRT1 by boosting NAD+ levels and SIRT1 induces the AMPK activator [52, 53]. Given its diverse functions in lipid homeostasis, SIRT1 is a potential therapeutic target to prevent obesity and liver steatosis and ameliorate cardiovascular diseases in obese individuals [54–56].
Similarly to SIRT1, SIRT2 facilitates lipolysis in WAT under nutrient deprivation by repressing transcriptional activity of PPARγ , and it attenuates lipid synthesis by suppressing ATP citrate lyase (ACLY), a building block for hepatic de novo lipogenesis , which might be biologically significant to fatty liver treatment. The link between SIRT2 and fatty acid oxidation appears to be elusive, and the development of diet-induced obesity in mice may be attributed to SIRT2 repression and attendant reduced β-oxidation .
SIRT3, SIRT4, and SIRT5
Current studies mainly indicate the role of SIRT3 in fatty acid oxidation. SIRT3 activates long chain acyl CoA dehydrogenase (LCAD) , a key enzyme involved in long-chain fatty acids oxidation, triggering β-oxidation in hepatocytes and skeletal muscle and also promotes ketogenesis via deacetylating and increasing the activity of the 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) in the liver .
In contrast to SIRT3, SIRT4 exhibits a negative regulatory role towards fatty acid oxidation. Under nutrient-replete condition, SIRT4 inhibits malonyl CoA decarboxylase (MCD) in muscle, an enzyme converting malonyl CoA to acetyl CoA, favoring lipid anabolism . In parallel, SIRT4 decreases PPARα and its target genes activities, consequently repressing fatty acid oxidation in liver . A more recent study highlighted a novel mechanism that deacetylating and destabilizing MTPα, a key enzyme in β-oxidation by SIRT4 may contribute to the pathogenesis of Nonalcoholic fatty liver disease (NAFLD) .
As a desuccinylase described above, SIRT5-dependent desuccinylation and activation of the rate-limiting ketogenic enzyme HMGCS2 may preferentially stimulate ketogenesis and reduced fatty acid oxidation was found in SIRT5 knockout mice . Consistently, downregulated expression of SIRT5 is detected in the liver of NAFLD patients .
Growing data noted that SIRT6 regulates fat metabolism as well. In the control of lipid storage, SIRT6 reduces the expression of PPARγ dependent genes in adipocytes and overexpression of SIRT6 reverses the detrimental outcome induced by high-fat diet in mice . Additionally, fatty liver and decreased fatty acid oxidation can be seen in liver-specific SIRT6 deletion mice , which implies its positive function upon lipogenesis and hepatic β-oxidation. A compelling study even presented that SIRT6 is associated with cholesterol homeostasis by negatively influencing lipogenic transcription factors SREBP1 and SREBP2 .
SIRT7, regarded as a deacetylase, is hypothesized to link lipid metabolism, even though the recent findings are perplexing and contradictory. The result of Shin et al. indicated Sirt7 knockout mice would develop liver steatosis due to deregulated ER stress , while Yoshizawa and colleagues concluded SIRT7-deficient mice were resistant to fatty liver and SIRT7 increases lipogenesis and fat accumulation . Accordingly, the underlying mechanism clearly merits further study.
Compared to quiescent cells, proliferating cells prefer to use crucial intermediates derived from tricarboxylic acid (TCA) cycle for biomass building that supports the cell growth and division. Thus, a process called anaplerosis is required to compensate the TCA cycle intermediates, for which glutamine is the main source. In particular, carbon from glutamine contributes to amino acid and fatty acid synthesis while the nitrogen from glutamine is used for nucleotide biosynthesis. During this replenishment, glutamine is firstly converted into glutamate by glutaminase that exists in two versions in mammals, kidney-type glutaminase (GLS) and liver-type glutaminase (GLS2). Glutamate is further converted to TCA cycle intermediates α-ketoglutarate either by glutamate dehydrogenase (GDH) or aminotransferases .
A succession of oncogenotypes instigate the upregulated glutamine metabolism [16–18]. The MYC may be the most common oncogene associated with glutamine metabolic rewiring. The oncogenic transcription factor c-Myc, which is known to stimulate cell proliferation through miRNAs regulation, was found to transcriptionally repress miR-23a and miR-23b resulting in a greater expression of their target protein GLS  and an enhanced glutamine-fuelled anaplerosis.
Apart from affected by many oncogenic mutations, glutamine enzymes are also controlled through post-translational modifications. SIRT3 might be associated with glutamine metabolism by augmenting the activities of GDH  and GLS2  through deacetylation. SIRT4, as mentioned above, inhibits GDH activity by ADP-ribosylation and consequently mediates reduction in glutamine metabolism, which appears to be tumor suppressive as discussed below. Interestingly, SIRT5 might be involved in glutamine metabolism by inhibitory desuccinylating GLS .
Clearly, the nuclear sirtuins possess a special place in glucose and lipid metabolism by enhancing or compromising the specific transcriptional program, while SIRT2 and mitochondrial sirtuins mainly aim at metabolic enzymes in response to various nutrient conditions. Most sirtuins are generally expected to promote catabolism such as gluconeogenesis and lipid oxidation and counteract anabolism including glycolysis, lipogenesis, adipogenesis and glutaminolysis. Consistent with this hypothesis, they are potentially involved in treatment of several metabolic diseases and even perhaps MYC-driven tumors (mitochondrial sirtuins).
Sirtuins in DNA repair
Recent studies have highlighted a unique feature of SIRT1 in regulating DNA damage repair as well as its role in maintaining telomere length and genomic stability [78–80]. Upon genotoxic stress, SIRT1 moves from silent promoters to sites of DNA damage, deacetylating histones H1 (Lys26) and H4 (Lys16) and contributing to the recruitment of DNA damage factors [81–84]. SIRT1 is recruited to DSBs in an ATM kinase-dependent manner . This recruitment is important for r-H2AX foci formation and accumulation of the DDR-related proteins such as Rad51, NBS1 and BRCA1 at the breaks.
Important role for SIRT1 in DNA damage repair includes DSB repair by HR [81, 86–88]. SIRT1 promotes HR by deacetylating WRN, a member of the RecQ DNA helicase family with functions in maintenance of genomic stability. Another studies have reported that SIRT1 interacts with telomere in vivo and SIRT1 overexpressed mice display increased HR DNA repair throughout the entire genome . Moreover, SIRT1 is also involved in NHEJ DNA repair. Deacetylation of Ku70 by SIRT1 enhances Ku70-dependent DNA repair and inhibits mitochondrial apoptosis after genotoxic stimuli. SIRT1-dependent KAP1 deacetylation also positively regulates NHEJ . Results establish the functional significance of KAP1 deacetylation in the DDR, highlighting a potential SIRT1-KAP1 regulatory mechanism for DSB repair that is independent from modulating the infrastructure of the chromatin. Finally, SIRT1 can regulate NER by deacetylating and activating xeroderma pigmentosum A and C proteins (XPA and XPC) upon UV damage. Deacetylated XPA and XPC recognize DNA SSBs and recruit other NER factors at the breaks for DNA repair .
Also, hMOF plays an important role in DDR, cell cycle progression, and cell growth [90, 91]. hMOF and TIP60, are SIRT1 substrates. The deacetylation of the enzymatic domains of hMOF and TIP60 by SIRT1 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins. Immediately following DNA damage, the binding of SIRT1 to hMOF and TIP60 is transiently interrupted, with corresponding hMOF/TIP60 hyperacetylation. Lysine-to-arginine mutations in SIRT1-targeted lysines on hMOF and TIP60 repress DNA DSB repair and inhibit the ability of hMOF/TIP60 to induce apoptosis in response to DNA DSB. Together, these findings uncover novel pathways in which SIRT1 dynamically interacts with and provide additional mechanistic insights by which SIRT1 regulates DDR.
SIRT2 is initially illustrated to be implicated in mitotic progression and function as a cell cycle regulator . Recently several studies highlighted the critical roles of SIRT2 in genome stability and DDR. During mitosis SIRT2 maintains genome integrity by deacetylating CDH1 and CDC20, co-activators of anaphase promoting complex/cyclosome (APC/C), and regulating APC/C activity . Through the deacetylation of H4K16Ac and the histone methyltransferase (HMT) PR-Set7, SIRT2 modulates H4K20 monomethylation deposition that is paramount in genome stability and DNA repair . Most recently, a study revealed SIRT2 is essential for the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase checkpoint pathway (a pathway maintains genome integrity) and deacetylates CDK9 and ATR-interacting protein (ATRIP) in response to replication stress [95, 96].
SIRT3 and SIRT4
SIRT3, SIRT4 and SIRT5, as mentioned above, reside in the mitochondria, where they control numerous aspects of mitochondrial metabolism. Beyond metabolic targets, SIRT3 has been shown to regulate the production of reactive oxygen species (ROS) from mitochondria by multiple mechanisms. For example, SIRT3 deacetylates and activates isocitrate dehydrogenase 2 (IDH2) and manganese superoxide dismutase (MnSOD) , which maintains cellular ROS homeostasis. SIRT3 also deacetylates numerous components of the electron transport chain, suggesting that SIRT3 could directly suppress ROS production . In this regard, SIRT3 loss increases cellular ROS levels, contributing to genomic and mitochondrial DNA instability, and SIRT3 KO mice develop estrogen receptor and progesterone receptor-positive mammary tumors .
The roles and importance of the mtDNA repair mechanisms and pathways in the protection against carcinogenesis, aging, and other human diseases have been increasingly recognized in the past decade. SIRT3 impacts the repair of mtDNA through its ability to deacetylate OGG1, a DNA glycosylase important in BER, and that loss of SIRT3 results in increases of acetylation, degradation of OGG1 and a decrease of the incision activity of this enzyme and promotes stress-induced apoptosis .
Importantly, SIRT3 can bind and deacetylate Ku70 in response to DNA damage , suggesting that SIRT3 might be involved in Ku70-dependent DNA repair.
SIRT4 is the most highly induced sirtuins in response to DNA damage stimuli and represses glutamine consumption without affecting glucose uptake, resulting in a decrease in the incorporation of glutamine into the tricarboxylic acid (TCA) cycle intermediates. This metabolic response contributes to cell cycle arrest of damaged cells and promotes the repair of damaged DNA. Indeed, loss of SIRT4 impaired DNA damage-induced cell cycle arrest and resulted in accumulation of DNA damage, and SIRT4 KO MEFs possessed more aneuploidy and exhibited an increased genomic instability.
SIRT6, a NAD + −dependent deacetylase and ADP-ribosyltransferase, plays a critical role in numerous DNA repair pathways. The first clues to the function of SIRT6 came from SIRT6 knockout mice. These SIRT6-deficient mice develop striking degenerative phenotypes and dramatic metabolic defects, some of which overlap with pathologies observed in premature aging . SIRT6 was shown to mediate histone (H3K9, H3K56) deacetylation and ultimately maintain the integrity of telomeric chromatin, defects of which likely accounts for the aging like phenotype [103, 104]. At the cellular level, SIRT6 deficiency leads to genomic instability and hypersensitivity to certain forms of genotoxic damage, suggesting its important role in DDR .
SIRT6 was initially proposed to work on BER, because the DNA damage sensitivities of SIRT6-deficient cells could be rescued by over-expression of the rate-limiting enzymes in BER . But the definitive role for SIRT6 in BER remains poorly understood. Recently Xu et al. has reported that SIRT6 regulates BER in a PARP1-depdendent manner . H wang et al. further proved that SIRT6 interacts with and stimulates two major BER enzymes (MYH and APE1) and also interacts with the Rad9–Rad1–Hus1 checkpoint clamp which stimulates almost every enzyme in the BER .
Besides BER, SIRT6 is also involved in DNA DSB repair such as HR and NHEJ. McCord et al. demonstrated that SIRT6 recruits and stabilizes DNA-dependent protein kinase (DNA-PK) to DSBs in turn promoting NHEJ repair . SIRT6 also stimulates the poly-ADP-ribosyltransferase activity of PARP1 (a protein involved in both double-strand break repair and BER), enhancing NHEJ and HR DNA repair . In addition, the chromatin remodeling factor SNF2H is recruited to DSBs by SIRT6, which provides proper docking sites for downstream DDR factors and allow efficient DNA repair . Taken together, SIRT6 modulates DNA repair pathways at multiple layers.
The role of SIRT7 in regulating DNA damage remains largely dormant for years until recently Vazquez and colleagues uncovered a novel function of SIRT7 in DNA repair . They noted that genome homeostasis is disrupted in the absence of SIRT7 and SIRT7 promotes DNA repair by deacetylating lysine 18 of histoneH3 (H3K18Ac) at DNA damage sites and then recruiting NHEJ repair factor 53BP1.
To conclude, SIRT1 and SIRT6 both pave the way for DNA repair partly through histone deacetylation at DNA break sites and then triggering recruitment of multiple repair factors. Besides the histone modifications, they also directly modulate non-histone substrates including DNA repair enzymes and other repair factors. When it comes to mitochondrial sirtuins, things turn out to be more intriguing. SIRT3 affects the genome and mitochondrial DNA stability by maintaining ROS homeostasis and even participate in the mtDNA repair pathways. And SIRT4 is appreciated to ensure proper DNA repair by dampening glutamine metabolism and initiating cell cycle arrest.
Sirtuins in cancer
It’s now widely believed that sirtuins regulate numerous processes that appear to be awry in cancer cells. The function of sirtuins are characterized as tumor suppressor and/or oncogene, depending on various genetic context, tumor type and stage. As detailed below, we mainly focus on the regulatory roles of sirtuins regarding DNA repair and cancer-related metabolism.
SIRT1’s role in carcinogenesis appears to be opposing and complicated. On one hand, SIRT1 was found to be tumorigenic in various human cancer [112–117], which is consistent with its anti-apoptotic activities via p53 and FOXO transcription factors in response to stress . In parallel, SIRT1 was shown to exert an essential role toward the oncogenic signaling mediated by the estrogen receptor-α (ERα) in breast cancer cells .
On the other hand, a collection of in vivo mouse models provided evidence that SIRT1 maintains genetic stability in normal cells and decelerates tumor formation [81, 115, 120]. Indeed, a decreased SIRT1 level in breast cancer is associated with BRCA1 mutations, suggesting it as a tumor suppressor. This anti-cancerogenic role could be explained by SIRT1-mediated suppression of the antiapoptotic gene survivin and it is also compatible with SIRT1’s genome stabilizing functions . Interestingly, SIRT1 turned out to be transcriptionally up-regulated by BRCA1, which is best known for its central role as a surveillance factor in DSB repair .
Accordingly, this context-dependent role of SIRT1 represents a target for selective killing of cancer versus non-cancer cells , and a recent drug screening approach has led to the identification of a potent SIRT1/2 inhibitory substance with potential use in cancer therapy .
Given the fact SIRT2 maintains genomic stability as discussed above, this sirtuin mainly functions as a tumor suppressor. Notably, it has been revealed that SIRT2 is also linked with cancer metabolism and promotes tumor growth. SIRT2 can regulate the activities of HIF-1α, phosphoglycerate mutase (PGAM) and glucose-6-phosphate dehydrogenase (G6PD) [125–127], which either stimulates glycolytic energy production or coordinates glycolysis and biomass production.
Decreased expression of SIRT2 can be observed in glioma, liver cancer, and esophageal and gastric adenocarcinomas [128, 129]. By contrast, SIRT2 has negative implications in certain types of cancer including acute myeloid leukemia , pancreatic cancer, neuroblastoma , high-grade human HCC and prostate cancer [132, 133]. Interestingly, SIRT2 functions as both tumor suppressor and oncogene dependent on different tumor grade in breast cancer .
SIRT3 appears to be a tumor suppressor mainly through its ability to repress reactive oxygen species (ROS) and HIF-1α [34, 135], which fights against metabolic switch towards aerobic glycolysis. In line with this, up-regulation of SIRT3 inhibited the cell growth of oral squamous cell carcinoma (OSCCs) and decreased the levels of basal reactive oxygen species (ROS) in both OSCC lines . Furthermore, a recent study revealed that SIRT3 negatively regulates pancreatic tumor growth by restraining malate-aspartate NADH shuttle, which is critical to sustain glycolysis in tumor cells, via deacetylating glutamate oxaloacetate transaminase (GOT2) . However, in specific type of cancer, SIRT3 turns out to be an oncogene and promote tumorigenensis [138, 139].
SIRT4 mRNA level was reduced in several human cancers, such as small cell lung carcinoma , gastric cancer , breast cancer and leukemia . And lower SIRT4 expression is associated with shorter survival time in lung tumor patients . A recent study has also showed that SIRT4 is a crucial regulator of the stress resistance in cancer cells and SIRT4 loss sensitizes cells to DNA damage or ER stress . Indeed, the activation of mammalian target of rapamycin complex 1 (mTORC1) has been demonstrated to be associated with increased glutamine metabolism through mechanically inhibiting SIRT4 .
Simply put, by reducing the activity of GDH, SIRT4 elicits the inhibition of glutamine anaplerosis and the attendant halt of cell proliferation that provides opportunity for DNA damage repair. Therefore, SIRT4 may attenuate the tumorigenesis by repressing glutamine metabolism and/or genomic instability [145–147].
SIRT5 has been considered as a potential oncogene by suppressing PDH, which may facilitate aerobic glycolysis . In support of this notion, SIRT5 is overexpressed in non-small cell lung cancer  and ovarian carcinoma . In accord with other sirtuins, SIRT5 is also emerged as a tumor suppressor in squamous cell carcinoma  and endometrial carcinoma .
SIRT6 is regarded as a tumor suppressor partly due to its pivotal role in cancer metabolism. Studies show SIRT6 represses aerobic glycolysis in cancer cells and SIRT6 deficiency contributes to tumor formation even without any oncogene activation , indicating the glucose metabolic reprogramming is not a mere consequence of tumorigenesis but also one of its main drivers. The avid glucose take up in SIRT6-deficient cells is due to the fact that SIRT6 binds and co-represses HIF-1α transcriptional activity which suppresses the expression of several key glycolytic genes . In addition, loss of SIRT6 leads to the increasing glutamine metabolism and ribosomal gene expression which are the later events in the tumorigenic process. Decreased H3K56 deacetylation at the promoter region by SIRT6 might account for that . Recently Zhang et al. show that SIRT6 inhibits hepatic gluconeogenesis via interacting with p53 and promotes glucose homeostasis .
As with SIRT1, SIRT6 plays both tumor suppressing and promoting roles. SIRT6 expression is downregulated in head and neck squamous cell carcinoma, colon, pancreatic, liver and non-small cell lung cancers [151, 155–157]. Conversely, increased SIRT6 expression has been reported in human skin squamous cell carcinoma and pancreatic, prostate and breast cancers, which suggests a poor prognosis and chemotherapy resistance [158–161].
Although received comparatively less attention than other sirtuins, SIRT7 appears to have several features that are critical for human cancers. Recent studies reported that SIRT7 has tumor promoting activities. In this regard, SIRT7 is found to be an oncogene in hepatocellular carcinoma, gastric cancer and colorectal cancer, and depletion of SIRT7 suppresses tumor growth [162–164]. Strikingly, overexpression of this sirtuin protects tumor cells against genotoxic damage and facilitates cell survival, suggesting the possibility that SIRT7 acts an oncogenic role by enhancing genome integrity in tumor cells .
To sum up, the dichotomous roles of sirtuins in cancer largely revolve around their functions in DNA damage response and cancer metabolism. In general, tumor-suppressive sirtuins inhibit metabolic shift to glycolysis and glutaminolysis, which are both distinct metabolic changes in cancer cells. And they are engaged in tumorigenesis partly through inducing aerobic glycolysis or sustaining genome stability in tumor cells.
Extensive studies over the past few years have pointed out that sirtuins are involved in processes including energy metabolism, genome integrity and carcinogenesis. Remarkably, several sirtuins play a dual role in cancer depending on various tumor types, stages and microenvironment. Thus, deciphering the underlying mechanisms and conditions which enabling their opposing role in cancer may be one of the main challenges and of tremendous therapeutic significance. Also, further work will be needed to dissect whether or how sirtuins connect and coordinate different hallmarks of cancer such as genomic instability, deregulated cell metabolism and aberrant tumor microenvironment.
We thank Shuang Liu for discussion and proofreading the manuscript. We apologize to colleagues whose work has not been described due to space limitations.
This work was supported by the National Basic Research Program of China [2015CB553903(Y.Tao)]; the National Natural Science Foundation of China [81372427 and 81672787(Y.Tao)] and the Fundamental Research Funds for the Central Universities [YC2016712 (X.Zhang)].
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ZM and XZ were major contributors in writing the manuscript. JY and JH helped to draft the manuscript. YT designed and revised the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. This manuscript has been read and approved by all the authors, and not submitted or under consider for publication elsewhere.
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- Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253–95.PubMedPubMed CentralView ArticleGoogle Scholar
- Tanno M, Kuno A, Horio Y, Miura T. Emerging beneficial roles of sirtuins in heart failure. Basic Res Cardiol. 2012;107:273.PubMedPubMed CentralView ArticleGoogle Scholar
- Kiran S, Chatterjee N, Singh S, Kaul SC, Wadhwa R, Ramakrishna G. Intracellular distribution of human SIRT7 and mapping of the nuclear/nucleolar localization signal. FEBS J. 2013;280:3451–66.PubMedView ArticleGoogle Scholar
- Iwahara T, Bonasio R, Narendra V, Reinberg D. SIRT3 functions in the nucleus in the control of stress-related gene expression. Mol Cell Biol. 2012;32:5022–34.PubMedPubMed CentralView ArticleGoogle Scholar
- Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011;334:806–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, Kang Y, Shenk T, Cristea IM. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell. 2014;159:1615–25.PubMedPubMed CentralView ArticleGoogle Scholar
- Poljsak B, Milisav I. NAD+ as the link between oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity, and health span. Rejuvenation Res. 2016;19:406–13.View ArticleGoogle Scholar
- Verdin E. The many faces of sirtuins: coupling of NAD metabolism, sirtuins and lifespan. Nat Med. 2014;20:25–7.PubMedView ArticleGoogle Scholar
- Kazantsev AG, Outeiro TF. Editorial on special topic: sirtuins in metabolism, aging, and disease. Front Pharmacol. 2012;3:71.PubMedPubMed CentralView ArticleGoogle Scholar
- Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.PubMedPubMed CentralView ArticleGoogle Scholar
- WARBURG O. On the origin of cancer cells. Science. 1956;123:309–14.PubMedView ArticleGoogle Scholar
- Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.PubMedView ArticleGoogle Scholar
- Vander HM, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.View ArticleGoogle Scholar
- Fang JS, Gillies RD, Gatenby RA. Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol. 2008;18:330–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35:427–33.PubMedPubMed CentralView ArticleGoogle Scholar
- Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2013;153:840–54.PubMedPubMed CentralView ArticleGoogle Scholar
- Dang CV. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 2010;70:859–62.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18:207–19.PubMedPubMed CentralView ArticleGoogle Scholar
- Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–14.PubMedPubMed CentralView ArticleGoogle Scholar
- Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–8.PubMedView ArticleGoogle Scholar
- Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates JR, et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature. 2008;456:269–73.PubMedPubMed CentralView ArticleGoogle Scholar
- Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–8.PubMedView ArticleGoogle Scholar
- Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012;13:225–38.PubMedPubMed CentralView ArticleGoogle Scholar
- Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010;38:864–78.PubMedView ArticleGoogle Scholar
- Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem. 2012;287:3850–8.PubMedView ArticleGoogle Scholar
- Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A, et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 2006;4:e31.PubMedView ArticleGoogle Scholar
- Kitada M, Kume S, Kanasaki K, Takeda-Watanabe A, Koya D. Sirtuins as possible drug targets in type 2 diabetes. Curr Drug Targets. 2013;14:622–36.PubMedView ArticleGoogle Scholar
- Guo R, Liu B, Wang K, Zhou S, Li W, Xu Y. Resveratrol ameliorates diabetic vascular inflammation and macrophage infiltration in db/db mice by inhibiting the NF-kappaB pathway. Diab Vasc Dis Res. 2014;11:92–102.PubMedView ArticleGoogle Scholar
- Guo R, Liu W, Liu B, Zhang B, Li W, Xu Y. SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: an insight into endoplasmic reticulum stress response mechanism. Int J Cardiol. 2015;191:36–45.PubMedView ArticleGoogle Scholar
- Ma L, Fu R, Duan Z, Lu J, Gao J, Tian L, Lv Z, Chen Z, Han J, Jia L, Wang L. Sirt1 is essential for resveratrol enhancement of hypoxia-induced autophagy in the type 2 diabetic nephropathy rat. Pathol Res Pract. 2016;212:310–8.PubMedView ArticleGoogle Scholar
- Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011;43:33–44.PubMedPubMed CentralView ArticleGoogle Scholar
- Gomes P, Outeiro TF, Cavadas C. Emerging role of sirtuin 2 in the regulation of mammalian metabolism. Trends Pharmacol Sci. 2015;36:756–68.PubMedView ArticleGoogle Scholar
- Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol. 2008;382:790–801.PubMedView ArticleGoogle Scholar
- Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011;19:416–28.PubMedPubMed CentralView ArticleGoogle Scholar
- Caton PW, Richardson SJ, Kieswich J, Bugliani M, Holland ML, Marchetti P, Morgan NG, Yaqoob MM, Holness MJ, Sugden MC. Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients. Diabetologia. 2013;56:1068–77.PubMedView ArticleGoogle Scholar
- Zhang HH, Ma XJ, Wu LN, Zhao YY, Zhang PY, Zhang YH, Shao MW, Liu F, Li F, Qin GJ. Sirtuin-3 (SIRT3) protects pancreatic beta-cells from endoplasmic reticulum (ER) stress-induced apoptosis and dysfunction. Mol Cell Biochem. 2016;420:95–106.PubMedView ArticleGoogle Scholar
- Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, Maechler P, Verdin E. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem. 2007;282:33583–92.PubMedView ArticleGoogle Scholar
- Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006;126:941–54.PubMedView ArticleGoogle Scholar
- Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, Najjar R, Fitch M, Hellerstein M, Gibson BW, Verdin E. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell. 2015;59:321–32.PubMedPubMed CentralView ArticleGoogle Scholar
- Jukarainen S, Heinonen S, Ramo JT, Rinnankoski-Tuikka R, Rappou E, Tummers M, Muniandy M, Hakkarainen A, Lundbom J, Lundbom N, et al. Obesity is associated with low NAD(+)/SIRT pathway expression in adipose tissue of BMI-discordant monozygotic twins. J Clin Endocrinol Metab. 2016;101:275–83.PubMedView ArticleGoogle Scholar
- Dominy JJ, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, Ruan HB, Feldman J, Pierce K, Mostoslavsky R, et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell. 2012;48:900–13.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140:280–93.PubMedPubMed CentralView ArticleGoogle Scholar
- Shun CT, Lin SK, Hong CY, Lin CF, Liu CM. Sirtuin 6 modulates hypoxia-induced autophagy in nasal polyp fibroblasts via inhibition of glycolysis. Am J Rhinol Allergy. 2016;30:179–85.PubMedView ArticleGoogle Scholar
- Song MY, Wang J, Ka SO, Bae EJ, Park BH. Insulin secretion impairment in Sirt6 knockout pancreatic beta cells is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway. Sci Rep. 2016;6:30321.PubMedPubMed CentralView ArticleGoogle Scholar
- Hubbi ME, Hu H, Kshitiz, Gilkes DM, Semenza GL. Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem. 2013;288:20768–75.PubMedPubMed CentralView ArticleGoogle Scholar
- Yoshizawa T, Karim MF, Sato Y, Senokuchi T, Miyata K, Fukuda T, Go C, Tasaki M, Uchimura K, Kadomatsu T, et al. SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. Cell Metab. 2014;19:712–21.PubMedView ArticleGoogle Scholar
- Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 2010;24:1403–17.PubMedPubMed CentralView ArticleGoogle Scholar
- Tobita T, Guzman-Lepe J, Takeishi K, Nakao T, Wang Y, Meng F, Deng CX, Collin DLA, Soto-Gutierrez A. SIRT1 disruption in human fetal hepatocytes leads to increased accumulation of glucose and lipids. PLoS One. 2016;11:e149344.View ArticleGoogle Scholar
- Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado DOR, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004;429:771–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009;9:327–38.PubMedPubMed CentralView ArticleGoogle Scholar
- Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 2007;26:1913–23.PubMedPubMed CentralView ArticleGoogle Scholar
- Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458:1056–60.PubMedPubMed CentralView ArticleGoogle Scholar
- Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008;283:27628–35.PubMedPubMed CentralView ArticleGoogle Scholar
- Mariani S, Fiore D, Persichetti A, Basciani S, Lubrano C, Poggiogalle E, Genco A, Donini LM, Gnessi L. Circulating SIRT1 increases after intragastric balloon fat loss in obese patients. Obes Surg. 2016;26:1215–20.PubMedView ArticleGoogle Scholar
- Mariani S, Fiore D, Basciani S, Persichetti A, Contini S, Lubrano C, Salvatori L, Lenzi A, Gnessi L. Plasma levels of SIRT1 associate with non-alcoholic fatty liver disease in obese patients. Endocrine. 2015;49:711–6.PubMedView ArticleGoogle Scholar
- Mariani S, Costantini D, Lubrano C, Basciani S, Caldaroni C, Barbaro G, Poggiogalle E, Donini LM, Lenzi A, Gnessi L. Circulating SIRT1 inversely correlates with epicardial fat thickness in patients with obesity. Nutr Metab Cardiovasc Dis. 2016;26:1033–8.PubMedView ArticleGoogle Scholar
- Wang F, Tong Q. SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma. Mol Biol Cell. 2009;20:801–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013;51:506–18.PubMedPubMed CentralView ArticleGoogle Scholar
- Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S, Mirtschink P, Ukropcova B, Gasperikova D, Pedrazzini T, Krek W. Dietary obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev. 2012;26:259–70.PubMedPubMed CentralView ArticleGoogle Scholar
- Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464:121–5.PubMedPubMed CentralView ArticleGoogle Scholar
- Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010;12:654–61.PubMedPubMed CentralView ArticleGoogle Scholar
- Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell. 2013;50:686–98.PubMedPubMed CentralView ArticleGoogle Scholar
- Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, Cen Y, Jeong SM, Li X, Sauve AA, Haigis MC. SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation. Mol Cell Biol. 2013;33:4552–61.PubMedPubMed CentralView ArticleGoogle Scholar
- Guo L, Zhou SR, Wei XB, Liu Y, Chang XX, Liu Y, Ge X, Dou X, Huang HY, Qian SW, et al. Acetylation of mitochondrial trifunctional protein alpha-subunit enhances its stability to promote fatty acid oxidation and is decreased in NAFLD. Mol Cell Biol. 2016;36:2553–67.PubMedView ArticleGoogle Scholar
- Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, Guo A, Gut P, Sahu AK, Li B, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab. 2013;18:920–33.PubMedPubMed CentralView ArticleGoogle Scholar
- Wu T, Liu YH, Fu YC, Liu XM, Zhou XH. Direct evidence of sirtuin downregulation in the liver of non-alcoholic fatty liver disease patients. Ann Clin Lab Sci. 2014;44:410–8.PubMedGoogle Scholar
- Kanfi Y, Peshti V, Gil R, Naiman S, Nahum L, Levin E, Kronfeld-Schor N, Cohen HY. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell. 2010;9:162–73.PubMedView ArticleGoogle Scholar
- Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, Vazquez-Ortiz G, Jeong WI, Park O, Ki SH, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 2010;12:224–36.PubMedPubMed CentralView ArticleGoogle Scholar
- Elhanati S, Kanfi Y, Varvak A, Roichman A, Carmel-Gross I, Barth S, Gibor G, Cohen HY. Multiple regulatory layers of SREBP1/2 by SIRT6. Cell Rep. 2013;4:905–12.PubMedView ArticleGoogle Scholar
- Shin J, He M, Liu Y, Paredes S, Villanova L, Brown K, Qiu X, Nabavi N, Mohrin M, Wojnoonski K, et al. SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep. 2013;5:654–65.PubMedPubMed CentralView ArticleGoogle Scholar
- Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16:619–34.PubMedView ArticleGoogle Scholar
- Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.PubMedPubMed CentralView ArticleGoogle Scholar
- Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, Carson JJ, Tonelli M, Balloon AJ, Higbee AJ, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell. 2013;49:186–99.PubMedView ArticleGoogle Scholar
- Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, Steegborn C, Nowak T, Schutkowski M, Pellegrini L, et al. SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy. 2015;11:253–70.PubMedPubMed CentralView ArticleGoogle Scholar
- Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411:366–74.PubMedView ArticleGoogle Scholar
- Thompson LH, Schild D. Homologous recombinational repair of DNA ensures mammalian chromosome stability. Mutat Res. 2001;477:131–53.PubMedView ArticleGoogle Scholar
- Lieber MR. The mechanism of human nonhomologous DNA end joining. J Biol Chem. 2008;283:1–5.PubMedView ArticleGoogle Scholar
- Rajendran P, Ho E, Williams DE, Dashwood RH. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin Epigenetics. 2011;3:4.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhang B, Chen J, Cheng AS, Ko BC. Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells. PLoS One. 2014;9:e84931.PubMedPubMed CentralView ArticleGoogle Scholar
- Yamashita S, Ogawa K, Ikei T, Fujiki T, Katakura Y. FOXO3a potentiates hTERT gene expression by activating c-MYC and extends the replicative life-span of human fibroblast. PLoS One. 2014;9:e101864.PubMedPubMed CentralView ArticleGoogle Scholar
- Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell. 2008;135:907–18.PubMedPubMed CentralView ArticleGoogle Scholar
- Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell. 2004;16:93–105.PubMedView ArticleGoogle Scholar
- Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800.PubMedView ArticleGoogle Scholar
- Dobbin MM, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, Ahanonu B, Pao PC, Qiu Y, Zhao Y, Tsai LH. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci. 2013;16:1008–15.PubMedPubMed CentralView ArticleGoogle Scholar
- Jeong SM, Haigis MC. Sirtuins in cancer: a balancing act between genome stability and metabolism. Mol Cells. 2015;38:750–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Palacios JA, Herranz D, De Bonis ML, Velasco S, Serrano M, Blasco MA. SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell Biol. 2010;191:1299–313.PubMedPubMed CentralView ArticleGoogle Scholar
- Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmuller L, Gatz SA. Role of SIRT1 in homologous recombination. DNA Repair (Amst). 2010;9:383–93.View ArticleGoogle Scholar
- Yuan Z, Seto E. A functional link between SIRT1 deacetylase and NBS1 in DNA damage response. Cell Cycle. 2007;6:2869–71.PubMedView ArticleGoogle Scholar
- Lin YH, Yuan J, Pei H, Liu T, Ann DK, Lou Z. KAP1 deacetylation by SIRT1 promotes non-homologous end-joining repair. PLoS One. 2015;10:e123935.Google Scholar
- Gupta A, Guerin-Peyrou TG, Sharma GG, Park C, Agarwal M, Ganju RK, Pandita S, Choi K, Sukumar S, Pandita RK, et al. The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Mol Cell Biol. 2008;28:397–409.PubMedView ArticleGoogle Scholar
- Rea S, Xouri G, Akhtar A. Males absent on the first (MOF): from flies to humans. Oncogene. 2007;26:5385–94.PubMedView ArticleGoogle Scholar
- Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003;23:3173–85.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell. 2011;20:487–99.PubMedPubMed CentralView ArticleGoogle Scholar
- Serrano L, Martinez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, Beck DB, Kane-Goldsmith N, Tong Q, Rabanal RM, et al. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev. 2013;27:639–53.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhang H, Park SH, Pantazides BG, Karpiuk O, Warren MD, Hardy CW, Duong DM, Park SJ, Kim HS, Vassilopoulos A, et al. SIRT2 directs the replication stress response through CDK9 deacetylation. Proc Natl Acad Sci U S A. 2013;110:13546–51.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhang H, Head PE, Daddacha W, Park SH, Li X, Pan Y, Madden MZ, Duong DM, Xie M, Yu B, et al. ATRIP deacetylation by SIRT2 drives ATR checkpoint activation by promoting binding to RPA-ssDNA. Cell Rep. 2016;14:1435–47.PubMedPubMed CentralView ArticleGoogle Scholar
- Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12:662–7.PubMedView ArticleGoogle Scholar
- Bell EL, Guarente L. The SirT3 divining rod points to oxidative stress. Mol Cell. 2011;42:561–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17:41–52.PubMedPubMed CentralView ArticleGoogle Scholar
- Cheng Y, Ren X, Gowda AS, Shan Y, Zhang L, Yuan YS, Patel R, Wu H, Huber-Keener K, Yang JW, et al. Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress. Cell Death Dis. 2013;4:e731.PubMedPubMed CentralView ArticleGoogle Scholar
- Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol. 2008;28:6384–401.PubMedPubMed CentralView ArticleGoogle Scholar
- Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124:315–29.PubMedView ArticleGoogle Scholar
- Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008;452:492–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O, Chua KF. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009;8:2664–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Lombard DB, Schwer B, Alt FW, Mostoslavsky R. SIRT6 in DNA repair, metabolism and ageing. J Intern Med. 2008;263:128–41.PubMedPubMed CentralView ArticleGoogle Scholar
- Xu Z, Zhang L, Zhang W, Meng D, Zhang H, Jiang Y, Xu X, Van Meter M, Seluanov A, Gorbunova V, Mao Z. SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner. Cell Cycle. 2015;14:269–76.PubMedPubMed CentralView ArticleGoogle Scholar
- Hwang BJ, Jin J, Gao Y, Shi G, Madabushi A, Yan A, Guan X, Zalzman M, Nakajima S, Lan L, Lu AL. SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9-Rad1-Hus1 checkpoint clamp. BMC Mol Biol. 2015;16:12.PubMedPubMed CentralView ArticleGoogle Scholar
- McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, et al. SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging (Albany NY). 2009;1:109–21.View ArticleGoogle Scholar
- Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, Seluanov A, Gorbunova V. SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011;332:1443–6.PubMedView ArticleGoogle Scholar
- Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S, et al. SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell. 2013;51:454–68.PubMedPubMed CentralView ArticleGoogle Scholar
- Vazquez BN, Thackray JK, Simonet NG, Kane-Goldsmith N, Martinez-Redondo P, Nguyen T, Bunting S, Vaquero A, Tischfield JA, Serrano L. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. EMBO J. 2016;35:1488–503.PubMedView ArticleGoogle Scholar
- Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, Craddock C, Turner BM. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 2005;19:1751–9.PubMedView ArticleGoogle Scholar
- Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, Nagy TR. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 2007;67:6612–8.PubMedView ArticleGoogle Scholar
- Lim CS. SIRT1: tumor promoter or tumor suppressor? Med Hypotheses. 2006;67:341–4.PubMedView ArticleGoogle Scholar
- Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, Kim S, Xu X, Zheng Y, Chilton B, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008;14:312–23.PubMedPubMed CentralView ArticleGoogle Scholar
- Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M, Castelblanco E, Matias-Guiu X, Serrano M. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene. 2013;32:4052–6.PubMedView ArticleGoogle Scholar
- Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, Bhatia R, Chen W. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood. 2012;119:1904–14.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res. 2009;69:1702–5.PubMedView ArticleGoogle Scholar
- Santolla MF, Avino S, Pellegrino M, De Francesco EM, De Marco P, Lappano R, Vivacqua A, Cirillo F, Rigiracciolo DC, Scarpelli A, et al. SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer. Cell Death Dis. 2015;6:e1834.PubMedPubMed CentralView ArticleGoogle Scholar
- Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010;1:3.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, Lee MH, Xiao C, Vassilopoulos A, Chen W, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell. 2008;32:11–20.PubMedPubMed CentralView ArticleGoogle Scholar
- Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25:5864–74.PubMedView ArticleGoogle Scholar
- Ford J, Jiang M, Milner J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 2005;65:10457–63.PubMedView ArticleGoogle Scholar
- Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, McCarthy A, Appleyard V, Murray KE, Baker L, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13:454–63.PubMedPubMed CentralView ArticleGoogle Scholar
- Seo KS, Park JH, Heo JY, Jing K, Han J, Min KN, Kim C, Koh GY, Lim K, Kang GY, et al. SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene. 2015;34:1354–62.PubMedView ArticleGoogle Scholar
- Xu Y, Li F, Lv L, Li T, Zhou X, Deng CX, Guan KL, Lei QY, Xiong Y. Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase. Cancer Res. 2014;74:3630–42.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, Ling ZQ, Hu FJ, Sun YP, Zhang JY, et al. Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress. EMBO J. 2014;33:1304–20.PubMedPubMed CentralGoogle Scholar
- Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, Watanabe T, Ohama E, Tahimic CG, Kurimasa A, Oshimura M. Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun. 2003;309:558–66.PubMedView ArticleGoogle Scholar
- Peters CJ, Rees JR, Hardwick RH, Hardwick JS, Vowler SL, Ong CA, Zhang C, Save V, O’Donovan M, Rassl D, et al. A 4-gene signature predicts survival of patients with resected adenocarcinoma of the esophagus, junction, and gastric cardia. Gastroenterology. 2010;139:1995–2004.PubMedView ArticleGoogle Scholar
- Dan L, Klimenkova O, Klimiankou M, Klusman JH, van den Heuvel-Eibrink MM, Reinhardt D, Welte K, Skokowa J. The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells. Haematologica. 2012;97:551–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD, Ling D, Su SP, Nelson C, Chang DK, et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ. 2013;20:503–14.PubMedView ArticleGoogle Scholar
- Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, Song C, Cheung YS, Lai PB, Cheng SH, et al. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3beta/beta-catenin signaling. Hepatology. 2013;57:2287–98.PubMedView ArticleGoogle Scholar
- Hou H, Chen W, Zhao L, Zuo Q, Zhang G, Zhang X, Wang H, Gong H, Li X, Wang M, et al. Cortactin is associated with tumour progression and poor prognosis in prostate cancer and SIRT2 other than HADC6 may work as facilitator in situ. J Clin Pathol. 2012;65:1088–96.PubMedView ArticleGoogle Scholar
- McGlynn LM, Zino S, MacDonald AI, Curle J, Reilly JE, Mohammed ZM, McMillan DC, Mallon E, Payne AP, Edwards J, Shiels PG. SIRT2: tumour suppressor or tumour promoter in operable breast cancer? Eur J Cancer. 2014;50:290–301.PubMedView ArticleGoogle Scholar
- Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30:2986–96.PubMedPubMed CentralView ArticleGoogle Scholar
- Chen IC, Chiang WF, Liu SY, Chen PF, Chiang HC. Role of SIRT3 in the regulation of redox balance during oral carcinogenesis. Mol Cancer. 2013;12:68.PubMedPubMed CentralView ArticleGoogle Scholar
- Yang H, Zhou L, Shi Q, Zhao Y, Lin H, Zhang M, Zhao S, Yang Y, Ling ZQ, Guan KL, et al. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J. 2015;34:1110–25.PubMedPubMed CentralView ArticleGoogle Scholar
- Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D’Silva NJ, Kapila YL. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer-Am Cancer Soc. 2011;117:1670–8.Google Scholar
- Aury-Landas J, Bougeard G, Castel H, Hernandez-Vargas H, Drouet A, Latouche JB, Schouft MT, Ferec C, Leroux D, Lasset C, 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;21:1369–76.PubMedPubMed CentralView ArticleGoogle Scholar
- Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, van de Rijn M, Rosen GD, Perou CM, Whyte RI, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 2001;98:13784–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang Q, Wen YG, Li DP, Xia J, Zhou CZ, Yan DW, Tang HM, Peng ZH. Upregulated INHBA expression is associated with poor survival in gastric cancer. Med Oncol. 2012;29:77–83.PubMedView ArticleGoogle Scholar
- Choi YL, Tsukasaki K, O’Neill MC, Yamada Y, Onimaru Y, Matsumoto K, Ohashi J, Yamashita Y, Tsutsumi S, Kaneda R, et al. A genomic analysis of adult T-cell leukemia. Oncogene. 2007;26:1245–55.PubMedView ArticleGoogle Scholar
- Shedden K, Taylor JM, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL, Eschrich S, Jurisica I, Giordano TJ, Misek DE, et al. Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med. 2008;14:822–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Jeong SM, Hwang S, Seong RH. SIRT4 regulates cancer cell survival and growth after stress. Biochem Biophys Res Commun. 2016;470:251–6.PubMedView ArticleGoogle Scholar
- Carafa V, Nebbioso A, Altucci L. Sirtuins and disease: the road ahead. Front Pharmacol. 2012;3:4.PubMedPubMed CentralView ArticleGoogle Scholar
- Fernandez-Marcos PJ, Serrano M. Sirt4: the glutamine gatekeeper. Cancer Cell. 2013;23:427–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene. 2007;26:5489–504.PubMedView ArticleGoogle Scholar
- Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, Xie Z, Zhang Y, Zwaans BM, Skinner ME, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell. 2013;50:919–30.PubMedPubMed CentralView ArticleGoogle Scholar
- Lu W, Zuo Y, Feng Y, Zhang M. SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumour Biol. 2014;35:10699–705.PubMedView ArticleGoogle Scholar
- Kumar S, Lombard DB. Mitochondrial sirtuins and their relationships with metabolic disease and cancer. Antioxid Redox Signal. 2015;22:1060–77.PubMedPubMed CentralView ArticleGoogle Scholar
- Lai CC, Lin PM, Lin SF, Hsu CH, Lin HC, Hu ML, Hsu CM, Yang MY. Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumour Biol. 2013;34:1847–54.PubMedView ArticleGoogle Scholar
- Bartosch C, Monteiro-Reis S, Almeida-Rios D, Vieira R, Castro A, Moutinho M, Rodrigues M, Graca I, Lopes JM, Jeronimo C. Assessing sirtuin expression in endometrial carcinoma and non-neoplastic endometrium. Oncotarget. 2016;7:1144–54.PubMedGoogle Scholar
- Sebastian C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151:1185–99.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhang P, Tu B, Wang H, Cao Z, Tang M, Zhang C, Gu B, Li Z, Wang L, Yang Y, et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc Natl Acad Sci U S A. 2014;111:10684–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Zwaans BM, Lombard DB. Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming. Dis Model Mech. 2014;7:1023–32.PubMedPubMed CentralView ArticleGoogle Scholar
- Marquardt JU, Fischer K, Baus K, Kashyap A, Ma S, Krupp M, Linke M, Teufel A, Zechner U, Strand D, et al. Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients. Hepatology. 2013;58:1054–64.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim EJ, Juhnn YS. Cyclic AMP signaling reduces sirtuin 6 expression in non-small cell lung cancer cells by promoting ubiquitin-proteasomal degradation via inhibition of the Raf-MEK-ERK (Raf/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase) pathway. J Biol Chem. 2015;290:9604–13.PubMedPubMed CentralView ArticleGoogle Scholar
- Bauer I, Grozio A, Lasiglie D, Basile G, Sturla L, Magnone M, Sociali G, Soncini D, Caffa I, Poggi A, et al. The NAD + −dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem. 2012;287:40924–37.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu Y, Xie QR, Wang B, Shao J, Zhang T, Liu T, Huang G, Xia W. Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics. Protein Cell. 2013;4:702–10.PubMedPubMed CentralView ArticleGoogle Scholar
- Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yague E, Cavaco TB, Khongkow P, Man EP, Laohasinnarong S, et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013;34:1476–86.PubMedView ArticleGoogle Scholar
- Ming M, Han W, Zhao B, Sundaresan NR, Deng CX, Gupta MP, He YY. SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res. 2014;74:5925–33.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim W, Kim JE. SIRT7 an emerging sirtuin: deciphering newer roles. J Physiol Pharmacol. 2013;64:531–4.PubMedView ArticleGoogle Scholar
- Zhang S, Chen P, Huang Z, Hu X, Chen M, Hu S, Hu Y, Cai T. Sirt7 promotes gastric cancer growth and inhibits apoptosis by epigenetically inhibiting miR-34a. Sci Rep. 2015;5:9787.PubMedPubMed CentralView ArticleGoogle Scholar
- Yu H, Ye W, Wu J, Meng X, Liu RY, Ying X, Zhou Y, Wang H, Pan C, Huang W. Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res. 2014;20:3434–45.PubMedView ArticleGoogle Scholar
- Kiran S, Oddi V, Ramakrishna G. Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response. Exp Cell Res. 2015;331:123–41.PubMedView ArticleGoogle Scholar