Functions of Mammalian SIRT4 in Cellular Metabolism and Research Progress in Human Cancer

Overview

Journal Oncol Lett

Specialty Oncology

Date 2020 Aug 11

PMID 32774484

Citations 13

Authors

Changming Wang

Yan Liu

Yuyan Zhu

Chuize Kong

Affiliations

Soon will be listed here.

Abstract

Sirtuins are mammalian homologs of yeast silent information regulator two (SIRT) and are a highly conserved family of proteins, which act as nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases. The seven sirtuins (SIRT1-7) share a conserved catalytic core domain; however, they have different enzyme activities, biological functions, and subcellular localizations. Among them, mitochondrial SIRT4 possesses ADP-ribosyltransferase, NAD-dependent deacetylase, lipoamidase, and long-chain deacylase activities and can modulate the function of substrate proteins via ADP-ribosylation, delipoylation, deacetylation and long-chain deacylation. SIRT4 has been shown to play a crucial role in insulin secretion, fatty acid oxidation, amino acid metabolism, ATP homeostasis, apoptosis, neurodegeneration, and cardiovascular diseases. In addition, recent studies have demonstrated that SIRT4 acts as a tumor suppressor. Here, the present review summarizes the enzymatic activities and biological functions of SIRT4, as well as its roles in cellular metabolism and human cancer, which are described in the current literature.

Citing Articles

The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy.

Tang Y, Ju W, Liu Y, Deng Q Front Pharmacol. 2024; 15:1469830.

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Decreased sirtuin 4 levels promote cellular proliferation and invasion in papillary thyroid carcinoma.

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The dual role of sirtuins in cancer: biological functions and implications.

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SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.

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Sirtuin 2 promotes human cytomegalovirus replication by regulating cell cycle progression.

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References

Huynh F, Hu X, Lin Z, Johnson J, Hirschey M . Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds. J Inherit Metab Dis. 2017; 41(1):59-72. PMC: 5775063. DOI: 10.1007/s10545-017-0069-8. View

Negrini S, Gorgoulis V, Halazonetis T . Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010; 11(3):220-8. DOI: 10.1038/nrm2858. View

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

Argmann C, Auwerx J . Insulin secretion: SIRT4 gets in on the act. Cell. 2006; 126(5):837-9. DOI: 10.1016/j.cell.2006.08.031. View

Madsen A, Andersen C, Daoud M, Anderson K, Laursen J, Chakladar S . Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH. J Biol Chem. 2016; 291(13):7128-41. PMC: 4807294. DOI: 10.1074/jbc.M115.668699. View

Kumar S, Lombard D . For Certain, SIRT4 Activities!. Trends Biochem Sci. 2017; 42(7):499-501. PMC: 5518788. DOI: 10.1016/j.tibs.2017.05.008. View

Liszt G, Ford E, Kurtev M, Guarente L . Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem. 2005; 280(22):21313-20. DOI: 10.1074/jbc.M413296200. View

Anderson K, Huynh F, Fisher-Wellman K, Stuart J, Peterson B, Douros J . SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metab. 2017; 25(4):838-855.e15. PMC: 5444661. DOI: 10.1016/j.cmet.2017.03.003. View

Li S, Zheng W . Mammalian Sirtuins SIRT4 and SIRT7. Prog Mol Biol Transl Sci. 2018; 154:147-168. DOI: 10.1016/bs.pmbts.2017.11.001. View

10.

Zhou Z, McCARTHY D, OConnor C, Reed L, STOOPS J . The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proc Natl Acad Sci U S A. 2001; 98(26):14802-7. PMC: 64939. DOI: 10.1073/pnas.011597698. View

11.

Huang G, Cui F, Yu F, Lu H, Zhang M, Tang H . Sirtuin-4 (SIRT4) is downregulated and associated with some clinicopathological features in gastric adenocarcinoma. Biomed Pharmacother. 2015; 72:135-9. DOI: 10.1016/j.biopha.2015.04.013. View

12.

Nasrin N, Wu X, Fortier E, Feng Y, Bare O, Chen S . SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem. 2010; 285(42):31995-2002. PMC: 2952200. DOI: 10.1074/jbc.M110.124164. View

13.

Howitz K, Bitterman K, Cohen H, Lamming D, Lavu S, Wood J . Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425(6954):191-6. DOI: 10.1038/nature01960. View

14.

Klar A, Fogel S, MacLeod K . MAR1-a Regulator of the HMa and HMalpha Loci in SACCHAROMYCES CEREVISIAE. Genetics. 1979; 93(1):37-50. PMC: 1217836. DOI: 10.1093/genetics/93.1.37. View

15.

Gorrini C, Harris I, Mak T . Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013; 12(12):931-47. DOI: 10.1038/nrd4002. View

16.

van de Ven R, Santos D, Haigis M . Mitochondrial Sirtuins and Molecular Mechanisms of Aging. Trends Mol Med. 2017; 23(4):320-331. PMC: 5713479. DOI: 10.1016/j.molmed.2017.02.005. View

17.

Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y . Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J Biol Chem. 2007; 282(9):6823-32. DOI: 10.1074/jbc.M609554200. View

18.

Zeng J, Jiang M, Wu X, Diao F, Qiu D, Hou X . SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation. Aging Cell. 2018; 17(4):e12789. PMC: 6052465. DOI: 10.1111/acel.12789. View

19.

Wang Y, Guo Y, Gao J, Yuan X . Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage. Cancer Manag Res. 2018; 10:5591-5603. PMC: 6234993. DOI: 10.2147/CMAR.S172509. View

20.

Xiao Y, Zhang X, Fan S, Cui G, Shen Z . MicroRNA-497 Inhibits Cardiac Hypertrophy by Targeting Sirt4. PLoS One. 2016; 11(12):e0168078. PMC: 5161464. DOI: 10.1371/journal.pone.0168078. View