Sirtuin 1-3 Deacetylases: Biological Functions and Therapeutic Potential in Cancer

Öz

Cancer, which ranks second in the list of the deadliest diseases in the world after cardiovascular diseases, is a group of diseases whose incidence increases with age. However, the increased incidence in young patients in recent years has led researchers to search for novel and alternative treatments. The fact that members of the sirtuin (SIRT) deacetylase family, which are mammalian homologues of the Sir2 gene in yeast, have important roles in the occurrence and treatment of aging-related diseases, such as type 2 diabetes, obesity, cardiovascular disease and cancer, has amplified interest to the understanding of the roles of these enzymes in recent years. SIRTs offer novel approaches in cancer treatment by regulating cellular events, such as DNA repair, apoptosis, metabolism, and aging. It is possible to alter the activity of these proteins, also known as nicotinamide adenine dinucleotide (NAD+) dependent Class III histone deacetylases, with specific SIRT activators and inhibitors. In this review, the biological roles of the three most studied members of SIRT proteins, SIRT1, SIRT2 and SIRT3, and the importance of new organic molecules that change the activities of these SIRTs in cancer treatment in the light of recent literature are discussed, and it was aimed to contribute to filling the lack of Turkish literature on this subject.

Anahtar Kelimeler

• Cancer
• sirtuin
• nicotinamide adenine dinucleotide (NAD+)
• apoptosis
• DNA repair

Proje Numarası

120C117

Sirtuin1-3 Deasetilazlar: Biyolojik Fonksiyonları ve Kanserde Terapötik Potansiyelleri

Öz

Dünya üzerinde en ölümcül hastalıklar listesinde kalp-damar hastalıklarından sonra ikinci sırada yer alan kanser, genel olarak yaşla birlikte görülme sıklığı artan bir hastalık grubudur. Bununla birlikte, son yıllarda genç hastalarda da görülme sıklığının artması, araştırmacıları yeni ve alternatif tedavi arayışlarına yönlendirmektedir. Mayadaki Sir2 geninin memelilerdeki homologları olan sirtuin (SIRT) deasetilaz ailesi, tip 2 diyabet, obezite, kalp-damar hastalıkları, bazı sinir hastalıkları ve kanser gibi yaşlanmayla birlikte görülme sıklığı artan birçok hastalığın ortaya çıkmasıyla ilişkilendirilmesi, son yıllarda bu enzimlerin biyolojik rollerinin anlaşılmasına olan ilgiyi arttırmıştır. SIRT’ler DNA onarımı, apoptozis, metabolizma ve yaşlanma gibi hücresel olayların düzenlenmesindeki rolleri nedeniyle kanser tedavisinde yeni yaklaşımlar sunmaktadır. Nikotinamid adenin dinükleotide (NAD+) bağımlı Sınıf III histon deasetilazlar olarak da bilinen bu proteinlerin aktivitesini özel SIRT aktivatör ve inhibitörlerle değiştirilmesi mümkündür. Bu derlemede, SIRT proteinlerinin en çok çalışılan üç üyesi SIRT1, SIRT2 ve SIRT3’ün biyolojik rolleri, kanser ile olan ilişkileri ve SIRT’lerin aktivitelerini değiştiren yeni organik moleküllerin kanser tedavisindeki önemini araştıran güncel araştırma makaleleri derlenmiş ve Türkçe literatür eksikliğini gidermeye katkı sağlamayı amaçlanmıştır.

Anahtar Kelimeler

• Kanser
• sirtuin
• nikotinamid adenin dinükleotid (NAD+)
• apoptozis
• DNA onarımı

Destekleyen Kurum

TÜBİTAK

Proje Numarası

120C117

Teşekkür

Bu derlemenin sorumlu yazarı 2247-A TÜBİTAK Ulusal Öncü Araştırmacılar programı (proje #120C117) ile desteklenmektedir.

Kaynakça

1. Alcain FJ, Villalba JM, 2009. Sirtuin activators. Expert Opinion on Therapeutic Patents, 19: 403-414.
2. Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D'Silva NJ, Kapila YL, 2011. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer, 117(8): 1670-1678.
3. Allison SJ, Milner J, 2007. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle, 6: 2669-2677.
4. Audrito V, Vaisitti T, Rossi D, Gottardi D, Arena G, Laurenti L, Deaglio S, 2011. Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Research, 71(13): 4473-4483.
5. Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA, 2001. Identification of a small molecule inhibitor of Sir2p. Proceedings of the National Academy of Sciences, 98: 15113-15118.
6. Blanc S, Schoeller D, Kemnitz J, Weindruch R, Colman R, Newton W, Wink K, Baum S, Ramsey J, 2003. Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction. The Journal of Clinical Endocrinology & Metabolism, 88(1): 16-23.
7. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME, 2004. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303: 2011-2015.
8. Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, Jarho E, Lahtela-Kakkonen M, Mai A, Altucci L, 2016. Sirtuin functions and modulation: from chemistry to the clinic. Clinical Epigenetics, 8: 61.

9. Chen G, Huang P, Hu C, 2020. The role of SIRT2 in cancer: A novel therapeutic target. The International Journal of Cancer, 147: 3297-3304.
10. Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S, Kaushal D, Cheng HL, Fischer MR, Stokes N, Murphy MM, Appella E, Alt FW, 2005. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metabolism, 2: 67-76.
11. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA, 2004. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 305: 390-392.
12. Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC, 2011. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell, 19(3): 416-28.
13. Fontana L, Klein S, 2007. Aging, adiposity, and calorie restriction. JAMA, 297: 986-994
14. Ford J, Jiang M, Milner J, 2005. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Research, 65: 10457-10463.
15. Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL, 2001. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. Journal of Biological Chemistry, 276(42): 38837-38843.
16. Herranz D, Maraver A, Cañamero M, Gómez-López G, Inglada-Pérez L, Robledo M, Castelblanco E, Matias-Guiu X, Serrano M, 2013. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene, 32(34): 4052-4056.
17. Holloszy JO, Fontana L, 2007. Caloric restriction in humans. Experimental Gerontology, 42(8): 709-712.
18. Hu J, Jing H, Lin H, 2014. Sirtuin inhibitors as anticancer agents. Future Medicinal Chemistry, 6: 945-966.
19. Huang S, Zhao Z, Tang D, Zhou Q, Li Y, Zhou L, Yin Y, Wang Y, Pan Y, Dorfman RG, Ling T, Zhang M, 2017. Downregulation of SIRT2 Inhibits Invasion of Hepatocellular Carcinoma by Inhibiting Energy Metabolism. Translational Oncology, 10: 917-927.
20. Huhtiniemi T, Suuronen T, Lahtela-Kakkonen M, Bruijn T, Jaaskelainen S, Poso A, Salminen A, Leppanen J, Jarho E, 2010. N(epsilon)-Modified lysine containing inhibitors for SIRT1 and SIRT2. Bioorganic & Medicinal Chemistry, 18: 5616-5625.
21. Imai S, Armstrong CM, Kaeberlein M, Guarente L, 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 403: 795-800.
22. Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, Yates JR, 3rd, Bordone L, Guarente L, Krainc D, 2011. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nature Medicine, 18: 159-165.
23. Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM, Cho MH, Park GH, Lee KH, 2007. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Experimental & Molecular Medicine, 39: 8-13.
24. Jeong JK, Moon MH, Lee YJ, Seol JW, Park SY, 2013. Autophagy induced by the class III histone deacetylase Sirt1 prevents prion peptide neurotoxicity. Neurobiology of Aging, 34: 146-156.
25. Kalle AM, Mallika A, Badiger J, Talukdar P, 2010. Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells. Biochemical and biophysical research communications, 401(1): 13-19.
26. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH, 2007. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. The EMBO Journal, 26: 3169-3179.
27. Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM, Vassilopoulos A, Ozden O, Park SH, Singh KK, Abdulkadir SA, Spitz DR, Deng CX, Gius D, 2010. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell, 17: 41-52.
28. Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, Ji J, Wang XW, Park SH, Cha YI, Gius D, Deng CX, 2011. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell, 20(4): 487-499.
29. Lane MA, Ingram DK, Roth GS, 1999. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicological Sciences, 52(2 Suppl):41-48.
30. Li Y, Liu T, Liao S, Li Y, Lan Y, Wang A, Wang Y, He B, 2015. A mini-review on Sirtuin activity assays. Biochemical and Biophysical Research Communications, 467: 459-466.
31. Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY, 2013. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Molecular Cell, 51: 506-518.
32. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W, 2001. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell, 107: 137-148.
33. Messaoudi I, Warner J, Fischer M, Park B, Hill B, Mattison J, Lane MA, Roth GS, Ingram DK, Picker LJ, Douek DC, Mori M, Nikolich-Zugich J, 2006. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proceedings of the National Academy of Sciences, 103(51): 19448-19453.
34. Michor F, Iwasa Y, Nowak MA, 2004. Dynamics of cancer progression. Nature Reviews Cancer, 4: 197-205.
35. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH, 2007. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature, 450: 712-716.
36. Ming M, Soltani K, Shea CR, Li X, He YY, 2015. Dual role of SIRT1 in UVB-induced skin tumorigenesis. Oncogene, 34(3), 357-363.
37. Minor RK, Baur JA, Gomes AP, Ward TM, Csiszar A, Mercken EM, Abdelmohsen K, Shin YK, Canto C, Scheibye-Knudsen M, Krawczyk M, Irusta PM, Martín-Montalvo A, Hubbard BP, Zhang Y, Lehrmann E, White AA, Price NL, Swindell WR, Pearson KJ, Becker KG, Bohr VA, Gorospe M, Egan JM, Talan MI, Auwerx J, Westphal CH, Ellis JL, Ungvari Z, Vlasuk GP, Elliott PJ, Sinclair DA, de Cabo R, 2011. SRT1720 improves survival and healthspan of obese mice. Scientific Reports, 1: 70.
38. Ozden O, Park SH, 2021. SIRT2 mediated downregulation of FOXM1 in response to TGFβ through the RAF-MEK-ERK signaling pathway in colon cancer. Archives of Biological Sciences, 73(2):257-64.
39. Ozden O, Park SH, Kim HS, Jiang H, Coleman MC, Spitz DR, Gius D, 2011. Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging (Albany NY), 3: 102-107.
40. Ozden O, Park SH, Wagner BA, Song HY, Zhu Y, Vassilopoulos A, Jung B, Buettner GR, Gius D, 2014. SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radical Biology and Medicine, 76: 163-172.
41. Ozden O, Tural K, 2018. Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease. Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics, Fumiaki Uchiumi (ed.), Bölüm:8, s.163-180, IntechOpen.
42. Özden Ö, 2015. SIRT2-JAK1 interaction decreases IL-6 induced inflammatory response in cancer cells. Journal of the Faculty of Veterinary Medicine, 21: 813-817.
43. Özden Ö, 2017. Deacetylation of Androgen Receptor by SIRT2 and its Dysregulation Promotes Pathogenesis and Progression of Prostate Cancer. Kafkas Journal of Medical Sciences 7(2): 97-101.
44. Park SH, Ozden O, Jiang H, Cha YI, Pennington JD, Aykin-Burns N, Spitz DR, Gius D, Kim HS, 2011. Sirt3, mitochondrial ROS, ageing, and carcinogenesis. International Journal of Molecular Sciences, 12: 6226-6239.
45. Park SH, Ozden O, Liu G, Song HY, Zhu Y, Yan Y, Zou X, Kang HJ, Jiang H, Principe DR, Cha YI, Roh M, Vassilopoulos A, Gius D, 2016. SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth. Cancer Research, 76: 3802-3812.
46. Park SH, Zhu Y, Ozden O, Kim HS, Jiang H, Deng CX, Gius D, Vassilopoulos A, 2012. SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. Translational Cancer Research, 1: 15-21.
47. Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, Arbiser JL, Walker DI, Jones DP, Gius D, Gupta MP, 2015. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nature Communications, 6: 6656.
48. Ponnusamy M, Zhou X, Yan Y, Tang J, Tolbert E, Zhao TC, Gong R, Zhuang S, 2014. Blocking sirtuin 1 and 2 inhibits renal interstitial fibroblast activation and attenuates renal interstitial fibrosis in obstructive nephropathy. Journal of Pharmacology and Experimental Therapeutics, 350: 243-256.
49. Rack JG, VanLinden MR, Lutter T, Aasland R, Ziegler M, 2014. Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform. Journal of Molecular Biology, 426: 1677-1691.
50. Reed JC, 2000. Mechanisms of apoptosis. The American Journal of Pathology, 157: 1415-1430.
51. Rotili D, Tarantino D, Carafa V, Lara E, Meade S, Botta G, Mai A, 2010. Identification of tri‐and tetracyclic pyrimidinediones as sirtuin inhibitors. ChemMedChem, 5(5): 674-677.
52. Sanchez-Fidalgo S, Villegas I, Sanchez-Hidalgo M, de la Lastra CA, 2012. Sirtuin modulators: mechanisms and potential clinical implications. Current Medicinal Chemistry, 19: 2414-2441.
53. Saunders LR, Verdin E, 2007. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene, 26: 5489-5504.
54. Siegel RL, Miller KD, Jemal A, 2015. Cancer statistics, 2015. CA: A Cancer Journal for Clinicians, 65: 5-29.
55. Siegel RL, Miller KD, Jemal A, 2019. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians, 69: 7-34.
56. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA, 2010. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell, 143: 802-812.
57. Song C, Zhao J, Fu B, Li D, Mao T, Peng W, Wu H, Zhang Y, 2017. Melatonin-mediated upregulation of Sirt3 attenuates sodium fluoride-induced hepatotoxicity by activating the MT1-PI3K/AKT-PGC-1α signaling pathway. Free Radical Biology and Medicine, 112: 616-630.
58. Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D, 2010. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Molecular Cell, 40: 893-904.
59. Tissenbaum HA, Guarente L, 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410: 227-230.
60. Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R, Reinberg D, 2006. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes & development, 20(10), 1256-1261.
61. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA, 2001. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell, 107: 149-159.
62. Villalba JM, Alcain FJ, 2012. Sirtuin activators and inhibitors. Biofactors, 38: 349-59.
63. Wang B, Ye Y, Yang X, Liu B, Wang Z, Chen S, Jiang K, Zhang W, Jiang H, Mustonen H, Puolakkainen P, Wang S, Luo J, Shen Z, 2020. SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases. EMBO Reports, 21(4):e48183.
64. Wang F, Nguyen M, Qin FX, Tong Q, 2007. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell, 6: 505-514.
65. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, Kim S, Xu X, Zheng Y, Chilton B, Jia R, Zheng ZM, Appella E, Wang XW, Ried T, Deng CX, 2008. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell, 14: 312-323.
66. Weinberg RA, 1996. How cancer arises. Scientific American, 275: 62-70.
67. Yang L, Han Y, Suarez Saiz F, Minden MD, 2007. A tumor suppressor and oncogene: the WT1 story. Leukemia, 21: 868-876.
68. Yasuda T, Takizawa K, Ui A, Hama M, Kagawa W, Sugasawa K, Tajima K, 2021. Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair. Genes Cells, 26: 328-335.
69. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW, 2004. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO Journal, 23: 2369-2380.
70. Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch R, 2000. Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. The FASEB Journal, 14(12): 1825-1836.
71. Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P, Xu YH, Dong B, Xiong Y, Lei QY, Guan KL, 2013. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell, 23: 464-476.
72. Zhou W, Ni TK, Wronski A, Glass B, Skibinski A, Beck A, Kuperwasser C, 2016. The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer. Cell Reports, 17(5): 1302-1317.
73. Zhu Y, Park SH, Ozden O, Kim HS, Jiang H, Vassilopoulos A, Spitz DR, Gius D, 2012. Exploring the electrostatic repulsion model in the role of Sirt3 in directing MnSOD acetylation status and enzymatic activity. Free Radical Biology and Medicine, 53: 828-833.