Digestive Diseases and Sciences

, Volume 62, Issue 8, pp 1872–1880 | Cite as

Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma

  • Serena De Matteis
  • Anna Maria Granato
  • Roberta Napolitano
  • Chiara Molinari
  • Martina Valgiusti
  • Daniele Santini
  • Francesco Giuseppe Foschi
  • Giorgio Ercolani
  • Umberto Vespasiani Gentilucci
  • Luca Faloppi
  • Mario Scartozzi
  • Giovanni Luca Frassineti
  • Andrea Casadei Gardini
Review

Abstract

Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD+)-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.

Keywords

Hepatocellular carcinoma Metabolism SIRT-3 Tumor suppressor 

Abbreviations

SIRT

Sirtuin

SOD2

Superoxide dismutase 2

HCC

Hepatocellular carcinoma

HBV

Hepatitis B virus

HCV

Hepatitis C virus

AIH

Autoimmune hepatitis

PBC

Primary biliary cholangitis

NASH

Nonalcoholic steatohepatitis

DM2

Type 2 diabetes mellitus

NAFLD

Nonalcoholic fatty liver disease

MnSOD

Superoxide dismutase 2

OSCC

Oral squamous cell carcinoma

NMNAT2

Nicotinamide mononucleotide adenylyltransferase 2

GC

Gastric cancer

MIAM

2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester

References

  1. 1.
    Guarente L. The many faces of sirtuins: sirtuins and the Warburg effect. Nat Med. 2014;20:24–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Chen Y, Fu LL, Wen X, et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis. 2014;5:e1047.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009;119:2758–2771.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Alhazzazi TY, Kamarajan P, Verdin E, Kapila YL. Sirtuin-3 (SIRT3) and the hallmarks of cancer. Genes Cancer. 2013;4:164–171.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cho EH. SIRT3 as a regulator of non-alcoholic fatty liver disease. J Lifestyle Med. 2014;4:80–85.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Teodoro JS, Duarte FV, Gomes AP, et al. Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: a possible role for SirT3 activation. Mitochondrion. 2013;13:637–646.CrossRefPubMedGoogle Scholar
  7. 7.
    Choudhury M, Jonscher KR, Friedman JE. Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. Aging (Albany NY). 2011;3:175–178.CrossRefGoogle Scholar
  8. 8.
    Stroffolini T, Trevisani F, Pinzello G, et al. Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance. Dig Liver Dis. 2011;43:875–880.CrossRefPubMedGoogle Scholar
  9. 9.
    Faloppi L, Scartozzi M, Maccaroni E, et al. Evolving strategies for the treatment of hepatocellular carcinoma: from clinical-guided to molecularly-tailored therapeutic options. Cancer Treat Rev. 2011;37:169–177.CrossRefPubMedGoogle Scholar
  10. 10.
    Bellissimo F, Pinzone MR, Cacopardo B, Nunnari G. Diagnostic and therapeutic management of hepatocellular carcinoma. World J Gastroenterol. 2015;21:12003–12021.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Weir HJ, Lane JD, Balthasar N. SIRT3: a central regulator of mitochondrial adaptation in health and disease. Genes Cancer. 2013;4:118–124.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255–262.CrossRefPubMedGoogle Scholar
  13. 13.
    Dhillon RS, Denu JM. Using comparative biology to understand how aging affects mitochondrial metabolism. Mol Cell Endocrinol. 2016. doi:10.1016/j.mce.2016.12.020.Google Scholar
  14. 14.
    Kim HS, Patel K, Muldoon-Jacobs K, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem. 2005;280:13560–13567.CrossRefPubMedGoogle Scholar
  16. 16.
    Sack MN, Finkel T. Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harb Perspect Biol. 2012;4:a013102. doi:10.1101/cshperspect.a013102.
  17. 17.
    Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell. 2017;16:4–16.CrossRefPubMedGoogle Scholar
  18. 18.
    Carafa V, Nebbioso A, Altucci L. Sirtuins and disease: the road ahead. Front Pharmacol. 2012;31:3–4.Google Scholar
  19. 19.
    Nogueiras R, Habegger KM, Chaudhary N, et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev. 2012;92:1479–1514.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hebert AS, Dittenhafer-Reed KE, Yu W, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell. 2013;49:186–199.CrossRefPubMedGoogle Scholar
  21. 21.
    Hirschey M, Shimazu T, Goetzman E, et al. SIRT3 regulates mitochondrial fatty acid oxidation via reversible enzyme deacetylation. Nature. 2010;464:121–125.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Buler M, Aatsinki SM, Izzi V, Hakkola J. Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism. PLoS ONE. 2012;7:e49863.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hirschey M, Shimazu T, Jing E, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell. 2011;44:177–190.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    He J, Hu B, Shi X, et al. Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase Sirt3. Mol Cell Biol. 2013;33:2047–2055.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Souza MR, Diniz F, Medeiros-Filho JE, Araújo MS. Metabolic syndrome and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol. 2012;49:89–96.CrossRefPubMedGoogle Scholar
  26. 26.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–1978.CrossRefPubMedGoogle Scholar
  27. 27.
    Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14:32–42.CrossRefPubMedGoogle Scholar
  28. 28.
    Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62:606–615.CrossRefPubMedGoogle Scholar
  29. 29.
    Chen TM, Lin CC, Huang PT, Wen CF. Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. J Gastroenterol Hepatol. 2011;26:858–865.CrossRefPubMedGoogle Scholar
  30. 30.
    Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108:881–891.CrossRefPubMedGoogle Scholar
  31. 31.
    Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int. 2010;30:750–758.CrossRefPubMedGoogle Scholar
  32. 32.
    Tao R, Coleman MC, Pennington JD, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010;40:893–904.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Finley LW, Carracedo A, Lee J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell. 2011;19:416–442.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Schumacker PT. SIRT3 controls cancer metabolic reprogramming by regulating ROS and HIF. Cancer Cell. 2011;19:299–300.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Koyama T, Kume S, Koya D, et al. SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells. Free Radic Bio Med. 2011;51:1258–1267.CrossRefGoogle Scholar
  36. 36.
    Alhazzazi TY, Kamarajan P, Joo N, et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer. 2011;117:1670–1678.CrossRefPubMedGoogle Scholar
  37. 37.
    Lai CC, Lin PM, Lin SF, et al. Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumour Biol. 2013;34:1847–1854.CrossRefPubMedGoogle Scholar
  38. 38.
    George J, Nihal M, Singh CK, Zhong W, Liu X, Ahmad N. Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma. J Invest Dermatol. 2016;136:809–818.CrossRefPubMedGoogle Scholar
  39. 39.
    Choi J, Koh E, Lee YS, et al. Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma. Biochem Biophys Res Commun. 2016;474:547–553.CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang L, Ren X, Cheng Y, et al. Identification of Sirtuin 3, a mitochondrial protein deacetylase, as a new contributor to tamoxifen resistance in breast cancer cells. Biochem Pharmacol. 2013;86:726–733.CrossRefPubMedGoogle Scholar
  41. 41.
    Xiang XY, Kang JS, Yang XC, et al. SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells. Int J Oncol. 2016;49:773–784.PubMedGoogle Scholar
  42. 42.
    Li H, Feng Z, Wu W, Li J, Zhang J, Xia T. SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2. Int J Oncol. 2013;43:1420–1430.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Xiao K, Jiang J, Wang W, et al. Sirt3 is a tumor suppressor in lung adenocarcinoma cells. Oncol Rep. 2013;30:1323–1328.PubMedGoogle Scholar
  44. 44.
    Allison SJ, Milner J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle. 2007;6:2669–2677.CrossRefPubMedGoogle Scholar
  45. 45.
    Liu C, Huang Z, Jiang H, Shi F. The sirtuin 3 expression profile is associated with pathological and clinical outcomes in colon cancer patients. Biomed Res Int. 2014;2014:871263.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Yang B, Fu X, Shao L, Ding Y, Zeng D. Aberrant expression of SIRT3 is conversely correlated with the progression and prognosis of human gastric cancer. Biochem Biophys Res Commun. 2014;443:156–160.CrossRefPubMedGoogle Scholar
  47. 47.
    Wang L, Wang WY, Cao LP. SIRT3 inhibits cell proliferation in human gastric cancer through down-regulation of Notch-1. Int J Clin Exp Med. 2015;8:5263–5271.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Marfe G, Tafani M, Indelicato M, et al. Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction. J Cell Biochem. 2009;106:643–650.CrossRefPubMedGoogle Scholar
  49. 49.
    Yu W, Denu RA, Krautkramer KA, et al. Loss of SIRT3 provides growth advantage for B cell malignancies. J Biol Chem. 2016;291:3268–3279.CrossRefPubMedGoogle Scholar
  50. 50.
    Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem. 2005;16:449–466.CrossRefPubMedGoogle Scholar
  51. 51.
    Faccioruso A, Villani R, Bellanti F, Mitarotonda D, Vendemiale G, Serviddio G. Mitochondrial signaling and hepatocellular carcinoma: molecular mechanisms and therapeutic implications. Curr Pharm Des. 2016;22:2689–2696.CrossRefGoogle Scholar
  52. 52.
    Yoon CY, Park MJ, Lee JS, et al. The histone deacetylase inhibitor trichostatin A synergistically resensitizes a cisplatin resistant human bladder cancer cell line. J Urol. 2001;185:1102–1111.CrossRefGoogle Scholar
  53. 53.
    Royce SG, Dang W, Yuan G, et al. Effects of the histone deacetylase inhibitor, trichostatin A, in a chronic allergic airways disease model in mice. Arch Immunol Ther Exp. 2012;60:295–306.CrossRefGoogle Scholar
  54. 54.
    Wang JX, Yi Y, Li YW, et al. Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection. BMC Cancer. 2014;14:297.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Casaril M, Corso F, Bassi A, Nicoli N, Bellisola G, Corrocher R. Decreased activity of scavenger enzymes in human hepatocellular carcinoma, but not in liver metastases. Int J Clin Lab Res. 1994;24:94–97.CrossRefPubMedGoogle Scholar
  56. 56.
    Liaw KY, Lee PH, Wu FC, Tsai JS, Lin-Shiau SY. Zinc, copper, and superoxide dismutase in hepatocellular carcinoma. Am J Gastroenterol. 1997;92:2260–2263.PubMedGoogle Scholar
  57. 57.
    Fabregat I, Roncero C, Fernández M. Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int. 2007;27:155–162.CrossRefPubMedGoogle Scholar
  58. 58.
    Song CL, Tang H, Ran LK, et al. Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3β/BCL2-associated X protein-dependent apoptotic pathway. Oncogene. 2016;35:631–641.CrossRefPubMedGoogle Scholar
  59. 59.
    Zhang CZ, Liu L, Cai M, et al. Low SIRT3 expression correlates with poor differentiation and unfavorable prognosis in primary hepatocellular carcinoma. PLoS ONE. 2012;7:e51703.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ren JH, Chen X, Zhou L, et al. Protective role of Sirtuin3 (SIRT3) in oxidative stress mediated by hepatitis B virus X protein expression. PLoS ONE. 2016;11:e0150961.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zhang YY, Zhou LM. Sirt3 inhibits hepatocellular carcinoma cell growth through reducing Mdm2-mediated p53 degradation. Biochem Biophys Res Commun. 2012;423:26–31.CrossRefPubMedGoogle Scholar
  62. 62.
    Tao NN, Zhou HZ, Tang H, et al. Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway. Oncotarget. 2016. doi:10.18632/oncotarget.10319.Google Scholar
  63. 63.
    Abdul NA, Nagiah S, Chuturgoon AA. Fusaric acid induces mitochondrial stress in human hepatocellular carcinoma (HepG2) cells. Toxicon. 2016;119:336–344.CrossRefGoogle Scholar
  64. 64.
    Li Y, Wang W, Xu X, Sun S, Xu X, Qu XJ. {2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) inhibited human hepatocellular carcinoma growth through upregulation of Sirtuin-3 (SIRT3). Biomed Pharmacother. 2015;69:125–132.CrossRefPubMedGoogle Scholar
  65. 65.
    Li Y, Wang W, Xu X, Sun S, Xu X, Qu XJ. {2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester inhibited hepatocellular carcinoma growth in bel-7402 cells and its resistant variants by activation of NOX4 and SIRT3. Biomed Res Int. 2015;2015:491205.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Serena De Matteis
    • 1
  • Anna Maria Granato
    • 2
  • Roberta Napolitano
    • 1
  • Chiara Molinari
    • 1
  • Martina Valgiusti
    • 3
  • Daniele Santini
    • 4
  • Francesco Giuseppe Foschi
    • 5
  • Giorgio Ercolani
    • 6
    • 7
  • Umberto Vespasiani Gentilucci
    • 8
  • Luca Faloppi
    • 9
  • Mario Scartozzi
    • 9
  • Giovanni Luca Frassineti
    • 3
  • Andrea Casadei Gardini
    • 3
  1. 1.Biosciences LaboratoryIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCSMeldolaItaly
  2. 2.Immunotherapy and Cell Therapy UnitIRST IRCCSMeldolaItaly
  3. 3.Department of Medical OncologyIRST IRCCSMeldolaItaly
  4. 4.Campus Bio-MedicoUniversity of RomeRomeItaly
  5. 5.Department of Internal MedicineOspedale per gli InfermiFaenzaItaly
  6. 6.Department of General SurgeryMorgagni-Pierantoni HospitalForlìItaly
  7. 7.Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
  8. 8.Internal Medicine and Hepatology UnitUniversity Campus Bio-MedicoRomeItaly
  9. 9.Medical Oncology, University HospitalUniversity of CagliariMonserrato, CagliariItaly

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