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Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules

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Abstract

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD+-dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity. As expected based on the biological effects of SIRT6 deacetylase activity, compound 1 increased histone 3 lysine 9 acetylation and the activity of glycolytic enzymes. Moreover, the fact that compound 1 enhanced SIRT6 deacylase activity was accompanied by an increased TNF-α release. In conclusion, new SIRT6 modulators with a lysine-like structure were identified, with differential effects on specific SIRT6 activities.

Graphic abstract

The novel SIRT6 modulator concomitantly inhibits deacetylase and enhances deacylase activity.

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Abbreviations

SIRT6:

Sirtuin 6

TNF-α:

Tumor necrosis factor α

HATU:

1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HBTU:

O-benzotriazol-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

DMF:

Dimethylformamide

DIPEA:

N,N-diisopropylethylamine

DCM:

Dichloromethane

TFA:

Trifluoroacetic acid

Q :

2,4-Dioxo-N-(4-(pyridin-3-yloxy)phenyl)-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

PFK:

Phosphofructokinase

PK:

Pyruvate kinase

LDH:

Lactate dehydrogenase

Fmoc:

9-Fluorenylmethoxycarbonyl

NMP:

N-methylpyrrolidone

References

  1. Feldman JL, Dittenhafer-Reed KE, Denu JM (2012) Sirtuin catalysis and regulation. J Biol Chem 287:42419–42427. https://doi.org/10.1074/jbc.R112.378877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bruzzone S, Parenti MD, Grozio A, Ballestrero A, Bauer I, Del Rio A, Nencioni A (2013) Rejuvenating sirtuins: the rise of a new family of cancer drug targets. Curr Pharm Des 19:614–623

    Article  CAS  Google Scholar 

  3. Jiang Y, Liu J, Chen D, Yan L, Zheng W (2017) Sirtuin inhibition: strategies, inhibitors, and therapeutic potential. Trends Pharmacol Sci 38:459–472. https://doi.org/10.1016/j.tips.2017.01.009

    Article  CAS  PubMed  Google Scholar 

  4. Feldman JL, Baeza J, Denu JM (2013) Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J Biol Chem 288:31350–31356. https://doi.org/10.1074/jbc.C113.511261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kugel S, Mostoslavsky R (2014) Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem Sci 39:72–81. https://doi.org/10.1016/j.tibs.2013.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H (2013) SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496:110–113. https://doi.org/10.1038/nature12038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bauer I, Grozio A, Lasigliè D, Basile G, Sturla L, Magnone M, Sociali G, Soncini D, Caffa I, Poggi A, Zoppoli G, Cea M, Feldmann G, Mostoslavsky R, Ballestrero A, Patrone F, Bruzzone S, Nencioni A (2012) The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem 287:40924–40937. https://doi.org/10.1074/jbc.M112.405837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Parenti MD, Grozio A, Bauer I, Galeno L, Damonte P, Millo E, Sociali G, Franceschi C, Ballestrero A, Bruzzone S, Del Rio A, Nencioni A (2014) Discovery of novel and selective SIRT6 inhibitors. J Med Chem 57:4796–4804. https://doi.org/10.1021/jm500487d

    Article  CAS  PubMed  Google Scholar 

  9. Tasselli L, Zheng W, Chua KF (2017) SIRT6: novel mechanisms and links to aging and disease. Trends Endocrinol Metab 28:168–185. https://doi.org/10.1016/j.tem.2016.10.002

    Article  CAS  PubMed  Google Scholar 

  10. Bae EJ (2017) Sirtuin 6, a possible therapeutic target for type 2 diabetes. Arch Pharm Res 40:1380–1389. https://doi.org/10.1007/s12272-017-0989-8

    Article  CAS  PubMed  Google Scholar 

  11. Lefort K, Brooks Y, Ostano P, Cario-André M, Calpini V, Guinea-Viniegra J, Albinger-Hegyi A, Hoetzenecker W, Kolfschoten I, Wagner EF, Werner S, Dotto GP (2013) A miR-34a-SIRT6 axis in the squamous cell differentiation network. EMBO J 32:2248–2263. https://doi.org/10.1038/emboj.2013.156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ming M, Han W, Zhao B, Sundaresan NR, Deng CX, Gupta MP, He YY (2014) SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res 74:5925–5933. https://doi.org/10.1158/0008-5472.CAN-14-1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lerrer B, Gertler AA, Cohen HY (2016) The complex role of SIRT6 in carcinogenesis. Carcinogenesis 37:108–118. https://doi.org/10.1093/carcin/bgv167

    Article  CAS  PubMed  Google Scholar 

  14. Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, Guo Y, Xie C (2016) Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget 7:40377–40386. https://doi.org/10.18632/oncotarget.9750

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sociali G, Galeno L, Parenti MD, Grozio A, Bauer I, Passalacqua M, Boero S, Donadini A, Millo E, Bellotti M, Sturla L, Damonte P, Puddu A, Ferroni C, Varchi G, Franceschi C, Ballestrero A, Poggi A, Bruzzone S, Nencioni A, Del Rio A (2015) Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics. Eur J Med Chem 102:530–539. https://doi.org/10.1016/j.ejmech.2015.08.024

    Article  CAS  PubMed  Google Scholar 

  16. Damonte P, Sociali G, Parenti MD, Soncini D, Bauer I, Boero S, Grozio A, Holtey MV, Piacente F, Becherini P, Sanguineti R, Salis A, Damonte G, Cea M, Murone M, Poggi A, Nencioni A, Del Rio A, Bruzzone S (2017) Bioorg Med Chem 25:5849–5858. https://doi.org/10.1016/j.bmc.2017.09.023

    Article  CAS  PubMed  Google Scholar 

  17. Kokkonen P, Rahnasto-Rilla M, Kiviranta PH, Huhtiniemi T, Laitinen T, Poso A, Jarho E, Lahtela-Kakkonen M (2012) ACS Med Chem Lett 3:969–974. https://doi.org/10.1021/ml300139n

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. He B, Hu J, Zhang X, Lin H (2014) Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors. Org Biomol Chem 12:7498–7502. https://doi.org/10.1039/c4ob00860j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. He Y, Yan L, Zang W, Zheng W (2015) Novel sirtuin inhibitory warheads derived from the N(ε)-acetyl-lysine analog L-2-amino-7-carboxamidoheptanoic acid. Org Biomol Chem 13:10442–10450. https://doi.org/10.1039/c5ob01721a

    Article  CAS  PubMed  Google Scholar 

  20. Liu J, Zheng W (2016) Cyclic peptide-based potent human SIRT6 inhibitors. Org Biomol Chem 14:5928–5935. https://doi.org/10.1039/c5ob02339d

    Article  CAS  PubMed  Google Scholar 

  21. Rahnasto-Rilla M, Tyni J, Huovinen M, Jarho E, Kulikowicz T, Ravichandran S, Bohr AV, Ferrucci L, Lahtela-Kakkonen M, Moaddel R (2018) Natural polyphenols as sirtuin 6 modulators. Sci Rep 8:4163. https://doi.org/10.1038/s41598-018-22388-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. You W, Rotili D, Li TM, Kambach C, Meleshin M, Schutkowski M, Chua KF, Mai A, Steegborn C (2017) Structural basis of sirtuin 6 activation by synthetic small molecules. Angew Chem Int Ed Engl 56:1007–1011. https://doi.org/10.1002/anie.201610082

    Article  CAS  PubMed  Google Scholar 

  23. Huang Z, Zhao J, Deng W, Chen Y, Shang J, Song K, Zhang L, Wang C, Lu S, Yang X, He B, Min J, Hu H, Tan M, Xu J, Zhang Q, Zhong J, Sun X, Mao Z, Lin H, Xiao M, Chin YE, Jiang H, Xu Y, Chen G, Zhang J (2018) Identification of a cellularly active SIRT6 allosteric activator. Nat Chem Biol 14:1118–1126. https://doi.org/10.1038/s41589-018-0150-0

    Article  CAS  PubMed  Google Scholar 

  24. Martín VI, Sarrión B, López-López M, López-Cornejo P, Robina I, Moyá ML (2015) Reversibility of the interactions between a novel surfactant derived from lysine and biomolecules. Colloids Surf B Biointerfaces 135:346–356. https://doi.org/10.1016/j.colsurfb.2015.07.076

    Article  CAS  PubMed  Google Scholar 

  25. Cardinali B, Lunardi G, Millo E, Armirotti A, Damonte G, Profumo A, Gori S, Iacono G, Levaggi A, Del Mastro L (2014) Trastuzumab quantification in serum: a new, rapid, robust ELISA assay based on a mimetic peptide that specifically recognizes trastuzumab. Anal Bioanal Chem 406:4557–4561. https://doi.org/10.1007/s00216-014-7842-4

    Article  CAS  PubMed  Google Scholar 

  26. Zhang X, Khan S, Jiang H, Antonyak MA, Chen X, Spiegelman NA, Shrimp JH, Cerione RA, Lin H (2016) Identifying the functional contribution of the defatty-acylase activity of SIRT6. Nat Chem Biol 12:614–620. https://doi.org/10.1038/nchembio.2106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Grozio A, Sociali G, Sturla L, Caffa I, Soncini D, Salis A, Raffaelli N, De Flora A, Nencioni A, Bruzzone S (2013) CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. J Biol Chem 288:25938–25949. https://doi.org/10.1074/jbc.M113.470435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cappelli E, Cuccarolo P, Stroppiana G, Miano M, Bottega R, Cossu V, Degan P, Ravera S (2017) Defects in mitochondrial energetic function compels Fanconi Anaemia cells to glycolytic metabolism. Biochim Biophys Acta Mol Basis Dis 1863:1214–1221. https://doi.org/10.1016/j.bbadis.2017.03.008

    Article  CAS  PubMed  Google Scholar 

  29. Feldman JL, Dittenhafer-Reed KE, Kudo N, Thelen JN, Ito A, Yoshida M, Denu JM (2015) Kinetic and structural basis for acyl-group selectivity and NAD(+) dependence in sirtuin-catalyzed deacylation. Biochemistry 54:3037–3050. https://doi.org/10.1021/acs.biochem.5b00150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280–293. https://doi.org/10.1016/j.cell.2009.12.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sociali G, Magnone M, Ravera S, Damonte P, Vigliarolo T, Von Holtey M, Vellone VG, Millo E, Caffa I, Cea M, Parenti MD, Del Rio A, Murone M, Mostoslavsky R, Grozio A, Nencioni A, Bruzzone S (2017) Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model. FASEB J 31:3138–3149. https://doi.org/10.1096/fj.201601294R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Italian Association for Cancer Research (AIRC) [Grants start-up #6266 and IG #19172 to A.D.R and IG #17736 and #22098 to A.N.]; by the FP7 Grants PANACREAS [GA #256986 to A.N., S.B. and I.R.] and ATHERO-B-CELL [GA #602114 to A.N.]; by the Italian Ministry of Health [Grant GR-2011-02347192], to A.N.; by the Fondazione Umberto Veronesi (to A.N. and to I.C.); by a 5 × 1000 2014 fund from the IRCCS Ospedale Policlinico San Martino (to A.N.); by the University of Genova (to A.N. and S.B.); by the BC161452P1 Grant of the Breast Cancer Research Program of the US Department of Defense (to A.N.); by “Ministerio de Economía y Competitividad” of Spain (CTQ2016-77270-R) to I.R. GS was recipient of a fellowship for young investigators granted by Collegio Ghislieri (Pavia, Italy). This work was also supported by FISM - Fondazione Italiana Sclerosi Multipla – cod. 2017/R/6 and financed or co-financed with the ‘5 per mille’ public funding (to S.B.). We thank Prof. Antonio De Flora for his careful reading of our manuscript.

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Author notes

  1. Alessia Grozio

    Present address: Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA

  2. Giovanna Sociali and Nara Liessi are equally contributing co-first authors.

Authors and Affiliations

  1. Department of Experimental Medicine, Section of Biochemistry, and CEBR, University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy

    Giovanna Sociali, Nara Liessi, Alessia Grozio, Andrea Benzi, Enrico Millo & Santina Bruzzone

  2. Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy

    Irene Caffa & Alessio Nencioni

  3. Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129, Bologna, Italy

    Marco Daniele Parenti & Alberto Del Rio

  4. Department of Experimental Medicine, Section of Anatomy, University of Genova, Via Leon Battista Alberti 2, 16132, Genoa, Italy

    Silvia Ravera

  5. Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132, Genoa, Italy

    Bruno Tasso

  6. IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy

    Alessio Nencioni

  7. Innovamol Srls, Viale A. Corassori 24, 41124, Modena, Italy

    Alberto Del Rio

  8. Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012, Seville, Spain

    Inmaculada Robina

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  1. Giovanna Sociali
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Correspondence to Enrico Millo or Santina Bruzzone.

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Sociali, G., Liessi, N., Grozio, A. et al. Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules. Mol Divers 24, 655–671 (2020). https://doi.org/10.1007/s11030-019-09971-2

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