Sirtuins and the Metabolic Hurdles in Cancer
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology Review Sirtuins and the Metabolic Hurdles in Cancer Natalie J. German and Marcia C. Haigis Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] (N.J.G.), [email protected] (M.C.H.) http://dx.doi.org/10.1016/j.cub.2015.05.012 The nutrient demands of cancer cannot be met by normal cell metabolism. Cancer cells undergo dramatic alteration of metabolic pathways in a process called reprogramming, characterized by increased nutrient up- take and re-purposing of these fuels for biosynthetic, bioenergetic or signaling pathways. Partitioning carbon sources toward growth and away from ATP production necessitates other means of generating energy for biosynthetic reactions. Additionally, cancer cell adaptations frequently lead to increased production of reac- tive oxygen species and lactic acid, which can be beneficial to cancer growth but also are potentially toxic and must be appropriately cleared. Sirtuins are a family of deacylases and ADP-ribosyltransferases with clear links to regulation of cancer metabolism. Through their unique ability to integrate cellular stress and nutrient status with coordination of metabolic outputs, sirtuins are well poised to play pivotal roles in tumor progres- sion and survival. Here, we review the multi-faceted duties of sirtuins in tackling the metabolic hurdles in can- cer. We focus on both beneficial and adverse effects of sirtuins in the regulation of energetic, biosynthetic and toxicity barriers faced by cancer cells. Introduction Here, we review the roles of sirtuins in the metabolic hurdles of It is more relevant than ever to understand how metabolism cancer. We will first overview sirtuin enzymatic activity and links influences tumor growth. Bioenergetic and biosynthetic depen- to cancer incidence and severity. Then we will discuss sirtuin- dencies of cancer cells are increasingly being realized as prom- mediated control of metabolic pathways with a focus on glucose ising candidates for therapeutic interventions in cancer [1–3]. metabolism, refilling of the tricarboxylic acid (TCA) cycle and A vast number of studies validate the notion that metabolic in defense against reactive oxygen species (ROS) in cancer. dysfunction is not just a consequence of cancer growth but rather Sirtuins coordinate many other processes linked to cancer, a driving factor in tumor progression [4,5]. Indeed, altered nutrient including DNA repair, metastasis, apoptosis and translation: for utilization enables tumor cells to fuel a number of processes, such reviews more comprehensively assessing those roles, we refer as amassing a pool of biosynthetic precursors, constructing the reader to other sources (such as [13,14,19]). signaling molecules, generating molecules for post-translational or epigenetic modifications, and maintaining pH and redox Connections between Sirtuin Activity and the Metabolic homeostasis [6,7]. Furthermore, metabolic dysfunction has posi- State tioned itself at the forefront of cancer research with the recogni- Sirtuin Enzymatic Activity tion of the undeniable connection between increased cancer inci- SIRT1–SIRT7 are a family of deacylases and ADP-ribosyltrans- dence and the background of obesity and metabolic disease, ferases that share a conserved catalytic core domain but vary pathologies that have reached epidemic proportions in the in subcellular localization and preferred substrates [20]. The dif- United States and much of the world [8–11]. It is critical to fully un- ferences between sirtuins lead to variations in the ultimate meta- derstand how tumor cells alter fuel usage and to identify path- bolic effect that is coordinated by each sirtuin [15]. SIRT1, SIRT6 ways that might promote or oppose this metabolic dysfunction. and SIRT7 are primarily nuclear and regulate transcription fac- Sirtuins are a highly conserved family of regulatory enzymes tors and histone modifications to coordinate gene expression that are well poised to play pivotal roles in tumor metabolism. programs that can direct the cellular metabolic state [21]. Cyto- The seven mammalian sirtuins (SIRT1–SIRT7) have the unique solic functions of SIRT1 have also been identified. SIRT2 is ability to integrate the cellular stress response with the coordina- largely cytosolic and coordinates microtubule dynamics as well tion of metabolic fitness and homeostasis [12,13]. The role of as the activity of transcription factors residing outside the nu- sirtuins as post-translational modifying enzymes may have orig- cleus [22,23]. Localization of SIRT3, SIRT4 and SIRT5 in the inated to allow survival under stress and low nutrient conditions, mitochondrial matrix enables these sirtuins to directly alter the and many of these functions have now been linked to growth activity of many metabolic enzymes [24]. regulation in the harsh conditions experienced by cancer cells Sirtuins catalyze nicotinamide adenine dinucleotide (NAD+)- [14–16]. In recent years, a number of studies have shown that sir- dependent deacylation or ADP-ribosylation reactions with vary- tuins not only coordinate cancer cell growth and survival, but ing degrees of substrate versatility [20]. Although originally also regulate the nutrient state of a tumor [17,18]. There is referred to as deacetylases, sirtuins are now classified more growing interest in pinpointing metabolic regulatory nodes that broadly as deacylases. This term accounts for the ability of can be targeted in cancer treatment and determining whether certain sirtuins to remove not only acetyl groups from lysine sirtuins specifically may be promising biomarkers or therapeutic residues, but also other acyl modifications, including propionyl, targets in cancer. butyryl, malonyl, succinyl and the lengthy fatty-acid-derived Current Biology 25, R569–R583, June 29, 2015 ª2015 Elsevier Ltd All rights reserved R569 Current Biology Review A Acyl groups O Acyl-lysine Deacylated O O NAD+ Nicotinamide residue lysine residue Lys Lys Lys O Acetyl Propionyl Butyryl O O NH2 O O O NH2 R NH +NH 3 HO + SIRT N HO Lys Lys ADP N ADP OH O + + Malonyl Succinyl O O N N O O C C OH OH OH O O Lys Lys O 2’-O-acyl- O 6 7 ADP ribose R Myristoyl Palmitoyl B Arginine ADP-ribosylated NAD+ Nicotinamide residue residue O O ADP O NH H2N NH + + 2 NH2 HN ADP N SIRT OH OH HN N + O + + NH2 HN OH OH N C N C O Current Biology Figure 1. Sirtuin-catalyzed reactions. (A) During deacylation reactions, sirtuins direct NAD+ to nucleophilically attack the acylated lysine residue, leading to removal of the acyl modification. NAD+ is cleaved in the process, forming nicotinamide and 2’-O-acyl ADP-ribose. Sirtuins can potentially remove diverse acyl modifications (inset) from lysine residues. (B) During ADP-ribosylation reactions, sirtuins use NAD+ to nucleophilically attack an arginine (shown) or cysteine residue. NAD+ is cleaved, resulting in release of nicotinamide and transfer of the ADP-ribose portion of NAD+ to the substrate residue. myristoyl and palmitoyl groups [25]. SIRT5, for example, is a cell death in response to puromycin. Of note, quantitative studies strong desuccinylase, and SIRT4 was recently reported to func- of OAADPR have been impeded by the rapid hydrolytic degrada- tion as a lipoamidase by removing lipoyl or biotinyl modifications tion of this molecule to ADP-ribose in cells [36]. The role of sir- from lysine residues [26]. Through these processes, sirtuins have tuin-derived metabolites is a promising and little studied area been shown to alter substrate activity, localization, stability and of sirtuin biology. protein–protein interactions [14]. Sirtuins and NAD+ Sensitivity Regardless of which type of substrate moiety is modified by Sirtuins are unique sensors of the metabolic state because their sirtuins, a similar NAD+-dependent reaction mechanism pro- NAD+-dependent enzymatic activity intrinsically couples their ceeds. During sirtuin-catalyzed deacylation (Figure 1A), NAD+ function to the metabolic status of the cell or organism [37–41]. nucleophilically attacks an acyl group of a substrate lysine. The According to the metabolic state of the cell, the ratio of NAD tog- resulting intermediate is cleaved to form 2’-O-acyl-ADP ribose gles between varying amounts of NAD+ and NADH [42]: NADH is (OAADPR) and nicotinamide, and the acyl group is removed a high-energy, reduced form of NAD that can donate electrons to from the lysine residue in the process. In sirtuin-catalyzed the electron transport chain, and NAD+ is the lower energy, ADP-ribosylation (Figure 1B), NAD+ similarly attacks a substrate oxidized counterpart required to fuel glycolysis. When the cell residue, typically an arginine residue [27], although cysteine res- uses oxidative metabolism, NADH generated by the TCA cycle idues are also candidate sites [28–30]. The ADP-ribose portion of and glycolysis donates electrons to complex I of the electron NAD+ is transferred to the substrate residue, yielding nicotin- transport chain (ETC). This contributes to a proton gradient amide as a side product [31,32]. that will ultimately produce ATP. Upon electron transfer, NADH The metabolic by-products of sirtuin activity have potential to is oxidized back to NAD+. In highly glycolytic cells with low accumulate and influence cellular biology. At high concentra- ETC function, NAD+ is alternatively regenerated from NADH via tions, nicotinamide inhibits sirtuin function [33]. Work by Grubi- lactate dehydrogenase (LDH) activity in order to sustain glycol- sha et al. [34] showed that pools of OAADPR generated by ysis. NAD+ can also be synthesized de novo from tryptophan certain sirtuins bind and inhibit the non-selective cation channel and vitamin B3 derivatives, or via salvage pathways using nico- TRPM2. This channel is normally activated by oxidative or nitra- tinamide or nicotinamide riboside. Thus, the NAD+:NADH ratio is tive stress as well as by the drug puromycin, which directly tar- affected by the cellular metabolic state, and changes in this ratio gets TRPM2 [34,35]. Activation of this channel leads to an influx have potential to impact sirtuin enzymatic activity.