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Sirtuins in Metabolism, DNA Repair and Cancer Zhen Mei1,2†, Xian Zhang1,2†, Jiarong Yi1,2, Junjie Huang1,2, Jian He1,2 and Yongguang Tao1,2*

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Sirtuins in Metabolism, DNA Repair and Cancer Zhen Mei1,2†, Xian Zhang1,2†, Jiarong Yi1,2, Junjie Huang1,2, Jian He1,2 and Yongguang Tao1,2* Mei et al. Journal of Experimental & Clinical Cancer Research (2016) 35:182 DOI 10.1186/s13046-016-0461-5 REVIEW Open Access Sirtuins in metabolism, DNA repair and cancer Zhen Mei1,2†, Xian Zhang1,2†, Jiarong Yi1,2, Junjie Huang1,2, Jian He1,2 and Yongguang Tao1,2* Abstract 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. Keywords: Sirtuin, DNA damage, Metabolism, Cancer, Post-translation modification Background NAD+ changes, sirtuins are proposed to work as stress Sirtuins, the highly conserved NAD + −dependent en- adaptors. Meanwhile, given their diverse enzymatic ac- zymes, are mammalian homologs of the yeast Sir2 gene tivities, they are described to play critical roles in regu- which has been known to promote replicative life span lating post-translational modifications (PTMs), among and mediate gene silencing in yeast [1]. The sirtuin fam- which acetylation is an important form. Sirtuins deacety- ily comprises seven proteins denoted as SIRT1-SIRT7, late a multitude of targets including histones, transcrip- which share a highly conserved NAD + −binding cata- tion factors, and metabolic enzymes. Taken together, lytic domain but vary in N and C-termini (Fig. 1). The sirtuins have been implicated in numerous cellular divergent terminal extensions account for their various processes including stress response, DNA repair, energy subcellular localization, enzymatic activity and binding metabolism, and tumorigenesis [8, 9]. targets. SIRT1, SIRT6, and SIRT7, are chiefly nuclear Aberrant cellular metabolism in cancer cells character- proteins, while SIRT3, SIRT4 and SIRT5 predominantly ized by elevated aerobic glycolysis and extensive glutami- reside in mitochondria and SIRT2 is primarily cytosolic nolysis [10] is essential to fuel uncontrolled proliferation (Fig. 1). But some of theses proteins are reported to and malignant tumor growth. The Warburg effect, translocate from their typical compartments under spe- which describes that tumor cells preferentially use glu- cific circumstances [2–4]. Besides the well-recognized cose for aerobic glycolysis in the presence of ample oxy- deacetylase function, sirtuins have also evolved as mono gen [11], has emerged as one of hallmarks of cancer. ADP ribosyltransferase, lipoamidase (SIRT4), demalony- Even though originally thought to be energy insufficient, lase and desuccinylase (SIRT5) [5, 6]. Warburg effect is now widely accepted to confer rapid The host cells are constantly subjected to oxidative, proliferation and invasive properties to tumor cells genotoxic and metabolic stress. The ratio of NAD+/ [12–14]. In parallel, many cancer cells exhibits enhanced NADH is correlated with stress resistance, oxidative glutamine metabolism and cannot survive in the absence metabolism and DNA repair [7]. Sensing intracellular of glutamine [15]. Recent studies have shown that a suc- cession of well-established oncogenic cues, including Myc, * Correspondence: [email protected] Ras or mammalian target of rapamycin complex 1 †Equal contributors (mTORC1) pathways play imperative roles in inducing 1 Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of glutaminolysis [16–18]. Besides metabolic reprogram- Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China ming, deregulated DNA-repair pathways and subsequent 2Cancer Research Institute, School of Basic Medicine, Central South genome instability appears to facilitate the acquisition of University, Changsha, Hunan 410078, China © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mei et al. Journal of Experimental & Clinical Cancer Research (2016) 35:182 Page 2 of 14 Name Structure Location 244 498 SIRT1 747aa Nucleus 65 340 SIRT2 389aa Cytoplasm 126 382 399aa Mitochondria SIRT3 45 314 314aa Mitochondria SIRT4 41 309 SIRT5 310aa Mitochondria 35 274 SIRT6 355aa Nucleus 90 331 SIRT7 400aa Nucleus Fig. 1 Schematic representation of seven mammalian sirtuins. The shaded area represents NAD+ - dependent catalytic domain. aa, amino acids tumorigenic mutations propitious to tumor growth and transcription of glycolytic genes by directly deacetylating cancer progression [19, 20]. transcription factor HIF1α [24] and also inhibits glycolytic Mounting evidence has shed light on that sirtuins play enzyme PGAM1 (phosphoglycerate mutase 1) through diverse parts in cancer [1]. In this review, we summarize deactylation [25]. SIRT1 is also implicated in glucose me- an overview and update on the function of sirtuins in tabolism by functioning as an insulin sensitizer. Through metabolism and DNA repair, and further touch on their transcriptionally repressing the uncoupling protein 2 roles in cancer mainly by affecting genome integrity and (UCP2), SIRT1 positively modulates glucose-stimulated in- cancer-associated metabolism. sulin secretion [26]. Accumulating evidence suggests that SIRT1 and SIRT1 activators can prevent and reverse insulin Sirtuins in metabolism resistance and diabetic complications, proven to be a prom- Glucose metabolism ising therapeutic target in type 2 diabetes (T2D) [27–30]. Glucose metabolism encompasses several processes implicating glucose uptake, utilization, storage and out- SIRT2 put, which needs elaborate coordination among the Compared to SIRT1, SIRT2 is predominantly a cytoplas- regulating hormone insulin and its counterpart such as mic protein and pretty abundant in adipocytes. SIRT2 glucagon. Sirtuins are verified to exert various impacts activates the rate-limiting enzyme phosphoenolpyruvate on gluconeogenesis, glycolysis, insulin secretion and sen- carboxykinase (PEPCK) via deacetylation and enhances sitivity bearing therapeutic potential to several metabolic gluconeogenesis during times of glucose deprivation diseases (Fig. 2). [31]. Meanwhile recent studies have proposed that, in SIRT1 regard to insulin sensitivity, SIRT2 may act specific and opposing roles in different tissues [32]. SIRT1 is the most conserved mammalian NAD + − dependent protein deacetylase that has emerged as a regulator of glucose metabolism. As for gluconeogenesis, SIRT3, SIRT4, and SIRT5 the role of SIRT1 is regarded as dual and intricate. In a Primarily located in mitochondria, SIRT3, SIRT4, and short-term fasting phase, SIRT1 induces decreased hep- SIRT5 sense and regulate the energy status in this organ- atic glucose production by suppressing CRTC2 (CREB- elle. Activating glutamate dehydrogenase (GDH), SIRT3 regulated transcription coactivator 2), a key mediator of facilitates gluconeogenesis from amino acids [33]. In early phase gluconeogenesis [21]. With the fasting phase addition, SIRT3 indirectly destabilizes transcription prolonged, SIRT1 deacetylates and activates both the factor HIF1α and subsequently inhibits glycolysis and transcription factor FOXO1 (forkhead box protein O1) glucose oxidation [34]. Intriguingly, recent studies have and its co-activator PGC1α (Peroxisome proliferator- shown that SIRT3 levels in pancreatic islets are reduced activated receptor gamma coactivator 1 α) [22, 23], in patients afflicted with type 2 diabetes [35] and SIRT3 which reinforces the gluconeogenic transcriptional pro- overexpression in pancreatic β-cells promotes insulin gram. In respect to glycolysis, SIRT1 attenuates the secretion and abrogates endoplasmic reticulum (ER) Mei et al. Journal of Experimental & Clinical Cancer Research (2016) 35:182 Page 3 of 14 glucose A gluconeogenensis glycolysis Phosphoenolpyruvate ( PEP) glutamine Cytosol SIRT2 PEPCK pyruvate oxaloacetate Mitochondria malate pyruvate GLS PDH SIRT4 PEP acetyl-coA glutamate oxaloacetate citrate SIRT4 GDH TCA Cycle isocitrate malate fumarate -ketoglutarate SIRT3 succinate B SIRT1 SIRT1 PGC1 SIRT6 FOXO1 Gluconeogenic genes HIF Nucleus Glycolytic genes SIRT1 SIRT6 Fig. 2 Overview of sirtuins in glucose metabolism. Selected pathways in nucleus, cytosol and mitochondria are depicted. a Located in cytoplasm, SIRT2 deacetylates the rate-limiting enzyme PEPCK and promotes gluconeogenesis during low nutrient condition. Both SIRT3 and SIRT4 target GDH in mitochondria but their enzymatic activities seem to be opposite. Besides GDH, SIRT4 also reduces PDH activity which converts pyruvate to acetyl CoA. SIRT5 facilitates glycolysis via glycolytic enzyme GAPDH and may disrupt glutamine metabolism through GLS. b In respect to the nuclear sirtuins, both SIRT1 and SIRT6 suppress the transcription factor HIF1α through different manners and subsequently attenuate
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