PERIODICUM BIOLOGORUM UDC 57:61 VOL. 116, No 4, 381–386, 2014 CODEN PDBIAD ISSN 0031-5362 Overview Sirtuins in tumorigenesis Abstract ANA KULIĆ1 MAJA SIROTKOVIĆ-SKERLEV1 Sirtuins (SIRT) are group of enzymes that require nicotinamide adenine NATALIJA DEDIĆ PLAVETIĆ2 dinucleotide (NAD+) to catalyze their reactions. These chemical compounds 2 BORISLAV BELEV have mono (ADP-ribosyl) transferase or deacetylases activities, and they can 3 SAŠA KRALIK-OGUIĆ be found in nearly all species. The mammalian sirtuin family is described MARIJA IVIĆ4 DAMIR VRBANEC2 by seven proteins, namely. Every group of sirtuins can be found in the dif- ferent regions of the cells; SIRT1 is predominantly nuclear, SIRT2 is lo- 1 Department of Oncology, Division of cated mainly in the cytoplasm (but it can shuttle between the nucleus and Pathophysiology and Experimental Oncology, the cytoplasm), SIRT3, SIRT4, and SIRT5 are mitochondrial proteins, University Hospital Center, Zagreb, Croatia, (SIRT3 can move from the nucleus to mitochondria during cellular stress), 2 Department of Oncology, Division of Medical SIRT6 and SIRT7 are nuclear sirtuins. Sirtuins have a lot of functions in Oncology, University Hospital Center and Zagreb different physiological processes such as gene repression, metabolic control, Medical School, Zagreb, Croatia apoptosis and cell survival, DNA repair, development, inflammation, neu- 3 Department of Laboratory Diagnostic, University roprotection, and healthy aging. Because of so many roles in physiological Hospital Center, Zagreb, Croatia, processes there is a huge interest not just in their functions but also in the 4 University Hospital Center and Zagreb Medical different compounds which can modify their functions. In this article we School, Zagreb, Croatia will focus on the role of sirtuins in tumorigenesis. Correspondence: Ana Kuli}, PhD Department of Oncology Division of Pathophysiology and Experimental Oncology University Hospital Center Zagreb Abbreviatians: Ki{pati}eva 12, HR- 10 000 Zagreb, Croatia SIRT – sirtuins E-mail: [email protected] NAD – nicotinamide ADP – adenosine diphosphate SNPs – single nucleotide polymorphisms Key words: sirtuins, cancer HDACs – histone deacetylases BMI – body mass index IDH2 – isocitrate dehydrogenase 2 GDH – glutamate dehydrogenase MnSOD – manganese superoxide dismutase VNTR – variable number tandem repeat TNF-a – tumor necrosis factor – alfa HIC1 – hypermethylated in cancer 1 FOXO 1 – Forkhead Box 1 FOXO 3 – Forkhead Box 3 Cdh1 – cadherin-1 Cdc20 – cell-division cycle protein 20 NEDD4 – neural precursor cell expressed developmentally down-regulated protein 4 AML – acute myeloid leukemia ROS – reactive oxygen species SOD2 – superoxide dismutase ETC – electron transport chain Received January 28, 2015. Skp2-S – phase kinase associated protein 2 Ana Kulić et al. Sirtuins INTRODUCTION Some of them are metabolism, aging, circadian clock regulation, pathophysiology of cancer, different inflam- ach sirtuin is characterized by approximately 275 matory conditions, nutritional behavior and obesity (5, amino acid conserved catalytic core region and by E 9). However, different types of sirtuins have different unique additional N-terminal and/or C-terminal sequenc- physiological function in the human body (Figure 1). es of variable length (1). Sirtuins are also known as class III histone deacetylases (HDACs), but their NAD+-depen- A recent study has reported associations of SIRT1 dency distinguishes them from other HDACs classes (2, 3). single nucleotide polymorphisms (SNPs) to the both obe- sity and body mass index (BMI) (10). SIRT1 is linked to The main sirtuin structure is characterized by a large the mitochondrial biogenesis in some tissues. It also stim- Rossman-fold domain (small part of compounds that is ulates fat and cholesterol catabolism in liver, skeletal typical for NAD+ binding proteins), a small zinc-binding muscle, and adipose tissue. domain, and a number of flexible loops (4). The large Rossmann-fold domain is characterized by six parallel b- Some recent studies have shown impaired regulation strands and a different number of b-helices, depending of SIRT2 in glioma. SIRT2 deletion can cause tumor on the type of sirtuin. Zinc-binding domain is character- occurrence; to the contrary its repletion may be used as a ized by the three antiparallel b-sheets, a variable b-helical tumor suppressive therapy (11). SIRT2-deficient mice de- region and a Zn2+cation (5). One of the most flexible re- velop gender-specific tumorigenesis; mammary tumor in gions of sirtuins is cofactor binding loop that connects females and hepatocellular carcinoma in males (12). the large and the small domain of enzyme (6, 7). This loop SIRT3 is presented in both mitochondria and nucleus. It conformation is dependent of the NAD+ or other reaction has main role in cellular energy metabolism and redox intermediates presence (the most important is 2-O-acetyl- regulation by deacetylating some mitochondrial proteins ADP-ribose) (8). such as acetyl-coenzyme A synthetase 2, isocitrate dehy- drogenase 2 (IDH2), glutamate dehydrogenase (GDH), manganese superoxide dismutase (MnSOD) (13). This OVERVIEW OF SIRTUINS FUNCTIONS sirtuin is the only one for which the correlation between Different roles of sirtuins have been described in a a polymorphism and prolonged human life has been great number of physiological or pathological conditions. proven (12). Figure 1. Location of the sirtuins in the cell. Their enzymatic activity, targets and substrates, function and involvment in various tumors are listed. 382 Period biol, Vol 116, No 4, 2014. Sirtuins Ana Kulić et al. It is known that a VNTR polymorphism in intron 5 resistance – associated protein 2(23). Additionally, SIRT1 of the SIRT3 gene has an allele-specific enhancer activity. promotes chemoresistance of tamoxifen – resistant breast The allele which has not enhancer activity is almost absent cancer cells by deacetylating FOXO1 (23). Increased ex- in males older than 90 years (14). pression of SIRT1 in advanced prostate cancer promotes cell invasion, migration and metastasis through matrix SIRT4 is localized in mitochondria and has a role in metalloproteinase -2 (24). A study of SIRT 1 in colorectal the regulation of cellular metabolic functions like insulin cancer showed a correlation with increased expression of secretion and fatty acid oxidation (15, 16). Some research c – Myc (25). SIRT1 is increased in breast carcinoma (26), has shown that SIRT4-depleted mice develop hyperinsu- colon cancer (27), lung cancer (28), prostate cancer (29), linemia and lung carcinoma (15, 17). SIRT5 is also mito- thyroid cancer (30), gastric cancer (31), liver cancer (32), chondrial sirtuin just like SIRT3 and SIRT 4. pancreatic cancer (33), ovarian and cervical cancers (34). Study of Nakagawa et al has shown that SIRT5-null On the other hand SIRT1 can prevent tumor growth mice can develop urea cycle defect and hyperammonemia through mechanisms of genomic protection by enabling after fasting (18). protection from stress, DNA reparation mechanism and SIRT6 is localized to the nucleus and has both deacet- regulation of metabolism. In addition, tumor cells them- ylase and ADP-ribosyltransferase activity. SIRT6 has been selves can prevent and control innate and adaptive im- shown to have a function in the regulation of transcrip- mune responses through inactivation of NF – kB tran- tion, genome stability, TNF-a secretion, metabolism and scription factor and reduction of surviving (35, 36). life expectancy (19). SIRT6 deficient mice die around 1 SIRT1 expression is reduced in human head and neck month after birth, showing premature aging phenotypes, squamous cell carcinoma and is associated with poor hypoglycemia, cardiac hypertrophy, hypersensitivity to prognosis in patients with this type of carcinoma (37). It DNA damage, and genomic instability (19). has been shown that inhibition of SIRT1 blocks p53- dependent apoptosis and DNA damage signaling which SIRT7 is the only sirtuin localized to the nucleolus and favors the growth of tumors. Further studies are needed it is linked to the ribosome biogenesis by the regulation in order to clarify the different roles of SIRT1 in tumor of transcription by positive regulation of RNA polymerase development. I transcription (20). SIRT7 deficiency induces apoptosis in human cells what indicates SIRT7 importance in cell survival. The results of some recent studies have shown SIRTUIN 2 AND TUMORIGENESIS that SIRT7-deficient mice die around 1 year after birth, In tumorigenesis, sirtuin 2 (SIRT2) can have the func- and develop inflammatory cardiomyopathy(21) . tion of a promoter or a suppressor according to the type of tumor. SIRT2 functions as a tumor suppressor through SIRTUINS AND TUMORIGENESIS the deacetylation of its substrates, such as FOXO1 (Fork- head Box 1)(38), FOXO 3a (Forkhead Box 3) (39), Cdh1 Sirtuins require special attention in cancer research (12), Cdc20 (12), H3K56 (40), or H4K16 (41). These are because of their biological role in metabolism, cell death, important molecules that maintain cell cycles, replication, regulation of genomic stability, inflammation and cellular and DNA damage response. Several studies have shown proliferation. Various studies have shown that studying that SIRT2 may function as a tumor suppressor by main- sirtuins can contribute to answering the question about taining mitotic integrity in a cell (11). It was shown that the connection between tumor development and aging. the expression of SIRT2 is down-regulated in