Startseite Lebenswissenschaften Citrate synthase desuccinylation by SIRT5 promotes colon cancer cell proliferation and migration
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

Citrate synthase desuccinylation by SIRT5 promotes colon cancer cell proliferation and migration

  • Mengmeng Ren , Xin Yang , Juntao Bie , Zhe Wang , Minghui Liu , Yutong Li , Genze Shao und Jianyuan Luo ORCID logo EMAIL logo
Veröffentlicht/Copyright: 11. August 2020

Abstract

Citrate synthase (CS), the rate-limiting enzyme in the tricarboxylic acid (TCA) cycle catalyzes the first step of the cycle, namely, the condensation of oxaloacetate and acetyl-CoA to produce citrate. The expression and enzymatic activity of CS are altered in cancers, but posttranslational modification (PTM) of CS and its regulation in tumorigenesis remain largely obscure. SIRT5 belongs to the nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase sirtuin family and plays vital roles in multiple biological processes via modulating various substrates. Here, we show that SIRT5 interacts with CS and that SIRT5 desuccinylates CS at the evolutionarily conserved residues K393 and K395. Moreover, hypersuccinylation of CS at K393 and K395 dramatically reduces its enzymatic activity and suppresses colon cancer cell proliferation and migration. These results provide experimental evidence in support of a potential therapeutic approach for colon cancer.


Corresponding author: Jianyuan Luo, Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, 100191, China; and Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 100191, Beijing, China, E-mail:

Award Identifier / Grant number: 81874147, 81671389

Acknowledgments

We thank the core facility at Peking University Health Science Center for mass-spectrometry analysis. This study was supported by the National Natural Science Foundation of China, No. 81874147, 81671389.

References

Anderson, A.S., Roberts, P.C., Frisard, M.I., McMillan, R.P., Brown, T.J., Lawless, M.H., Hulver, M.W., and Schmelz, E.M. (2013). Metabolic changes during ovarian cancer progression as targets for sphingosine treatment. Exp. Cell Res. 319: 1431–1442, https://doi.org/10.1016/j.yexcr.2013.02.017.Suche in Google Scholar PubMed PubMed Central

Boylston, J.A., Sun, J., Chen, Y., Gucek, M., Sack, M.N., and Murphy, E. (2015). Characterization of the cardiac succinylome and its role in ischemia-reperfusion injury. J. Mol. Cell. Cardiol. 88: 73–81, https://doi.org/10.1016/j.yjmcc.2015.09.005.Suche in Google Scholar PubMed PubMed Central

Chen, L., Liu, T., Zhou, J., Wang, Y., Wang, X., Di, W., and Zhang, S. (2014). Citrate synthase expression affects tumor phenotype and drug resistance in human ovarian carcinoma. PLoS One 9: e115708.10.1371/journal.pone.0115708Suche in Google Scholar PubMed PubMed Central

Chen, X.F., Tian, M.X., Sun, R.Q., Zhang, M.L., Zhou, L.S., Jin, L., Chen, L.L., Zhou, W.J., Duan, K.L., Chen, Y.J., et al. (2018). SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer. EMBO Rep. 19: e45124, https://doi.org/10.15252/embr.201745124.Suche in Google Scholar PubMed PubMed Central

Cui, X.X., Li, X., Dong, S.Y., Guo, Y.J., Liu, T., and Wu, Y.C. (2017). SIRT3 deacetylated and increased citrate synthase activity in PD model. Biochem. Biophys. Res. Commun. 484: 767–773.10.1016/j.bbrc.2017.01.163Suche in Google Scholar PubMed

Du, J., Zhou, Y., Su, X., Yu, J.J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J.H., Choi, B.H., et al. (2011). Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334: 806–809, https://doi.org/10.1126/science.1207861.Suche in Google Scholar PubMed PubMed Central

Fan, W. and Luo, J. (2010). SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol. Cell. 39: 247–258, https://doi.org/10.1016/j.molcel.2010.07.006.Suche in Google Scholar PubMed

Frye, R.A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273: 793–798, https://doi.org/10.1006/bbrc.2000.3000.Suche in Google Scholar PubMed

Guan, D., Lim, J.H., Peng, L., Liu, Y., Lam, M., Seto, E., and Kao, H.Y. (2014). Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death. Cell Death Dis. 5: e1340, https://doi.org/10.1038/cddis.2014.185.Suche in Google Scholar PubMed PubMed Central

Hirschey, M.D. and Zhao, Y.M. (2015). Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell. Proteomics 14: 2308–2315, https://doi.org/10.1074/mcp.r114.046664.Suche in Google Scholar

Lin, C.C., Cheng, T.L., Tsai, W.H., Tsai, H.J., Hu, K.H., Chang, H.C., Yeh, C.W., Chen, Y.C., Liao, C.C., and Chang, W.T. (2012). Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy. Sci. Rep. 2: 785, https://doi.org/10.1038/srep00785.Suche in Google Scholar

Li, F., He, X., Ye, D., Lin, Y., Yu, H., Yao, C., Huang, L., Zhang, J., Wang, F., Xu, S., et al. (2015). NADP+-IDH mutations promote hypersuccinylation that impairs mitochondria respiration and induces apoptosis resistance. Mol. Cell. 60: 661–675, https://doi.org/10.1016/j.molcel.2015.10.017.Suche in Google Scholar

Lin, Z.F., Xu, H.B., Wang, J.Y., Lin, Q., Ruan, Z., Liu, F.B., Jin, W., Huang, H.H., and Chen, X. (2013). SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem. Biophys. Res. Commun. 441: 191–195, https://doi.org/10.1016/j.bbrc.2013.10.033.Suche in Google Scholar

Lombard, D.B., Alt, F.W., Cheng, H.L., Bunkenborg, J., Streeper, R.S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., et al. (2007). Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27: 8807–8814, https://doi.org/10.1128/mcb.01636-07.Suche in Google Scholar

Lu, W., Zuo, Y., Feng, Y., and Zhang, M. (2014). SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumor Biol 35: 10699–10705.10.1007/s13277-014-2372-4Suche in Google Scholar

Lv, X.B., Liu, L., Cheng, C., Yu, B., Xiong, L., Hu, K., Tang, J., Zeng, L., and Sang, Y. (2015). SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer. Sci. Rep. 5: 17940.10.1038/srep17940Suche in Google Scholar

Ma, Y., Qi, Y., Wang, L., Zheng, Z., Zhang, Y., and Zheng, J. (2019). SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis. Free Radic. Biol. Med. 134: 458–467, https://doi.org/10.1016/j.freeradbiomed.2019.01.030.Suche in Google Scholar

Malecki, J., Jakobsson, M.E., Ho, A.Y.Y., Moen, A., Rustan, A.C., and Falnes, P.O. (2017). Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation. J. Biol. Chem. 292: 17950–17962, https://doi.org/10.1074/jbc.M117.808451.Suche in Google Scholar

Montal, E.D., Dewi, R., Bhalla, K., Ou, L., Hwang, B.J., Ropell, A.E., Gordon, C., Liu, W.J., DeBerardinis, R.J., Sudderth, J., et al. (2015). PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth. Mol Cell 60: 571–583, https://doi.org/10.1016/j.molcel.2015.09.025.Suche in Google Scholar

Mukherjee, A., Srere, P.A., and Frenkel, E.P. (1976). Studies of the mechanism by which hepatic citrate synthase activity increases in vitamin B12 deprivation. J. Biol. Chem. 251: 2155–2160.10.1016/S0021-9258(17)33669-4Suche in Google Scholar

Nakagawa, T.L., Lomb, D.J., Haigis, M.C., and Guarente, L. (2009). SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137: 560–570, https://doi.org/10.1016/j.cell.2009.02.026.Suche in Google Scholar PubMed PubMed Central

Nakamura, Y., Ogura, M., Ogura, K., Tanaka, D., and Inagaki, N. (2012). SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice. FEBS Lett. 586: 4076–4081, https://doi.org/10.1016/j.febslet.2012.10.009.Suche in Google Scholar PubMed

Nishida, Y., Rardin, M.J., Carrico, C., He, W., Sahu, A.K., Gut, P., Najjar, R., Fitch, M., Hellerstein, M., Gibson, B.W., et al. (2015). SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol. Cell. 59: 321–332, https://doi.org/10.1016/j.molcel.2015.05.022.Suche in Google Scholar PubMed PubMed Central

Park, J., Chen, Y., Tishkoff, D.X., Peng, C., Tan, M., Dai, L., Xie, Z., Zhang, Y., Zwaans, B.M., Skinner, M.E., et al. (2013). SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell. 50: 919–930, https://doi.org/10.1016/j.molcel.2013.06.001.Suche in Google Scholar PubMed PubMed Central

Rardin, M.J., He, W., Nishida, Y., Newman, J.C., Carrico, C., Danielson, S.R., Guo, A., Gut, P., Sahu, A.K., Li, B., et al. (2013). SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metabol. 18: 920–933, https://doi.org/10.1016/j.cmet.2013.11.013.Suche in Google Scholar PubMed PubMed Central

Sadhukhan, S., Liu, X., Ryu, D., Nelson, O.D., Stupinski, J.A., Li, Z., Chen, W., Zhang, S., Weiss, R.S., Locasaleb, J.W., et al. (2016). Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc. Natl. Acad. Sci. 113: 4320–4325, https://doi.org/10.1073/pnas.1519858113.Suche in Google Scholar PubMed PubMed Central

Schlichtholz, B., Turyn, J., Goyke, E., Biernacki, M., Jaskiewicz, K., Sledzinski, Z., and Swierczynski, J. (2005). Enhanced citrate synthase activity in human pancreatic cancer. Pancreas 30: 99–104, https://doi.org/10.1097/01.mpa.0000153326.69816.7d.Suche in Google Scholar PubMed

van der Mijn, J.C., Panka, D.J., Geissler, A.K., Verheul, H.M., and Mier, J.W. (2016). Novel drugs that target the metabolic reprogramming in renal cell cancer. Canc. Metabol. 4: 14, https://doi.org/10.1186/s40170-016-0154-8.Suche in Google Scholar PubMed PubMed Central

Wang, Y.Q., Wang, H.L., Xu, J., Tan, J., Fu, L.N., Wang, J.L., Zou, T.H., Sun, D.F., Gao, Q.Y., Chen, Y.X., et al. (2018). Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner. Nat. Commun. 9: 545, https://doi.org/10.1038/s41467-018-02951-4.Suche in Google Scholar PubMed PubMed Central

Weinert, B.T., Scholz, C., Wagner, S.A., Iesmantavicius, V., Su, D., Daniel, J.A., and Choudhary, C. (2013). Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep. 4: 842–851, https://doi.org/10.1016/j.celrep.2013.07.024.Suche in Google Scholar PubMed

Yang, X., Wang, Z., Li, X., Liu, B., Liu, M., Liu, L., Chen, S., Ren, M., Wang, Y., Yu, M., et al. (2018). SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation. Cancer Res. 78: 372–386, https://doi.org/10.1158/0008-5472.can-17-1912.Suche in Google Scholar

Ye, X., Niu, X., Gu, L., Xu, Y., Li, Z., Yu, Y., Chen, Z., and Lu, S. (2017). Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth. Oncotarget 8: 6984–6993.10.18632/oncotarget.14346Suche in Google Scholar PubMed PubMed Central

Yuan, C., Clish, C.B., Wu, C., Mayers, J.R., Kraft, P., Townsend, M.K., Zhang, M., Tworoger, S.S., Bao, Y., Qian, Z.R., et al. (2016). Circulating metabolites and survival among patients with pancreatic cancer. J. Natl. Cancer Inst. 108: djv409, https://doi.org/10.1093/jnci/djv409.Suche in Google Scholar PubMed PubMed Central

Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., Zhang, J., et al. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS One 14: e0211796, https://doi.org/10.1371/journal.pone.0211796.Suche in Google Scholar PubMed PubMed Central

Zhang, Y., Bharathi, S.S., Rardin, M.J., Lu, J., Maringer, K.V., Sims- Lucas, S., Prochownik, E.V., Gibson, B.W., and Goetzman, E.S. (2017). Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain. J. Biol. Chem. 292: 10239–10249.10.1074/jbc.M117.785022Suche in Google Scholar PubMed PubMed Central

Zhang, Y., Bharathi, S.S., Rardin, M.J., Uppala, R., Verdin, E., Gibson, B.W., and Goetzman, E.S. (2015). SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One 10: e0122297, https://doi.org/10.1371/journal.pone.0122297.Suche in Google Scholar PubMed PubMed Central

Zhou, L., Wang, F., Sun, R., Chen, X., Zhang, M., Xu, Q., Wang, Y., Wang, S., Xiong, Y., Guan, K.L., et al. (2016). SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep. 17: 811–822, https://doi.org/10.15252/embr.201541643.Suche in Google Scholar PubMed PubMed Central

Received: 2020-01-27
Accepted: 2020-03-31
Published Online: 2020-08-11
Published in Print: 2020-08-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Heruntergeladen am 7.1.2026 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2020-0118/pdf
Button zum nach oben scrollen