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The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration

Oncogene volume 34, pages 188–198 (2015)Cite this article

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Abstract

Rac1-GTPases serve as intermediary cellular switches, which conduct transient and constitutive signals from upstream cues, including those from Ras oncoproteins. Although the sirtuin1 (SIRT1) deacetylase is overexpressed in several human cancers and has recently been linked to cancer cell motility as a context-dependent regulator of multiple pathways, its role in Rac1 activation has not been reported. Similarly, SIRT2 has been demonstrated to be upregulated in some cancers; however, studies have also reported its role in tumor suppression. Here, we demonstrate that SIRT1 and SIRT2 positively regulate the levels of Rac1-GTP and the activity of T-cell lymphoma invasion and metastasis 1 (TIAM1), a Rac guanine nucleotide exchange factor (GEF). Transient inhibition of SIRT1 and SIRT2 resulted in increased acetylation of TIAM1, whereas chronic SIRT2 knockdown resulted in enhanced acetylation of TIAM1. SIRT1 regulates Dishevelled (DVL) protein levels in cancer cells, and DVL along with TIAM1 are known to augment Rac activation; however, SIRT1 or 2 has not been previously linked with TIAM1. We found that diminished sirtuin activity led to the disruption of the DVL1–TIAM1 interaction. We hence propose a model for Rac activation where SIRT1/2 positively modulates the DVL/TIAM1/Rac axis and promotes sustained pathway activation.

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References

  1. Heasman SJ, Ridley AJ . Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 2008; 9: 690–701.

    Article  CAS  Google Scholar 

  2. Bosco EE, Mulloy JC, Zheng Y . Rac1 GTPase: a ‘Rac’ of all trades. Cell Mol Life Sci 2009; 66: 370–374.

    Article  CAS  PubMed  Google Scholar 

  3. Rossman KL, Der CJ, Sondek J . GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 2005; 6: 167–180.

    Article  CAS  Google Scholar 

  4. Vigil D, Cherfils J, Rossman KL, Der CJ . Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 2010; 10: 842–857.

    Article  CAS  PubMed  Google Scholar 

  5. Habets GG, Scholtes EH, Zuydgeest D, van der Kammen RA, Stam JC, Berns A et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 1994; 77: 537–549.

    Article  CAS  PubMed  Google Scholar 

  6. Michiels F, Habets GG, Stam JC, van der Kammen RA, Collard JG . A role for Rac in Tiam1-induced membrane ruffling and invasion. Nature 1995; 375: 338–340.

    Article  CAS  PubMed  Google Scholar 

  7. Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol 2002; 4: 621–625.

    Article  CAS  PubMed  Google Scholar 

  8. Cook DR, Rossman KL, Der CJ . Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease. Oncogene (e-pub ahead of print 16 September 2013; doi:10.1038/onc.2013.362).

    Article  PubMed  Google Scholar 

  9. Minard ME, Herynk MH, Collard JG, Gallick GE . The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model. Oncogene 2005; 24: 2568–2573.

    Article  CAS  PubMed  Google Scholar 

  10. Ding Y, Chen B, Wang S, Zhao L, Chen J, Ding Y et al. Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patients. Int J Cancer 2009; 124: 653–658.

    Article  CAS  PubMed  Google Scholar 

  11. Liu H, Shi G, Liu X, Wu H, Fan Q, Wang X . Overexpression of Tiam1 predicts poor prognosis in patients with esophageal squamous cell carcinoma. Oncol Rep 2011; 25: 841–848.

    CAS  PubMed  Google Scholar 

  12. Michiels F, Stam JC, Hordijk PL, van der Kammen RA, Ruuls-Van SL, Feltkamp CA et al. Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and C-Jun NH2-terminal kinase activation. J Cell Biol 1997; 137: 387–398.

    Article  CAS  PubMed  Google Scholar 

  13. Fleming IN, Elliott CM, Collard JG, Exton JH . Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C. J Biol Chem 1997; 272: 33105–33110.

    Article  CAS  PubMed  Google Scholar 

  14. Hordijk PL, ten Klooster JP, van der Kammen RA, Michiels F, Oomen LC, Collard JG . Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science 1997; 278: 1464–1466.

    Article  CAS  PubMed  Google Scholar 

  15. Sander EE, van DS, ten Klooster JP, Reid T, van der Kammen RA, Michiels F et al. Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol 1998; 143: 1385–1398.

    Article  CAS  PubMed  Google Scholar 

  16. Malliri A, van der Kammen RA, Clark K, van d V, Michiels F, Collard JG . Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 2002; 417: 867–871.

    Article  CAS  Google Scholar 

  17. Woodcock SA, Rooney C, Liontos M, Connolly Y, Zoumpourlis V, Whetton AD et al. SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1. Mol Cell 2009; 33: 639–653.

    Article  CAS  Google Scholar 

  18. Buongiorno P, Pethe VV, Charames GS, Esufali S, Bapat B . Rac1 GTPase and the Rac1 exchange factor Tiam1 associate with Wnt-responsive promoters to enhance beta-catenin/TCF-dependent transcription in colorectal cancer cells. Mol Cancer 2008; 7: 73.

    Article  PubMed  Google Scholar 

  19. Haberland M, Montgomery RL, Olson EN . The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009; 10: 32–42.

    Article  CAS  PubMed  Google Scholar 

  20. Krusche CA, Wulfing P, Kersting C, Vloet A, Bocker W, Kiesel L et al. Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res Treat 2005; 90: 15–23.

    Article  CAS  Google Scholar 

  21. Weichert W, Roske A, Niesporek S, Noske A, Buckendahl AC, Dietel M et al. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res 2008; 14: 1669–1677.

    Article  CAS  Google Scholar 

  22. Brooks CL, Gu W . How does SIRT1 affect metabolism, senescence and cancer? Nat Rev Cancer 2009; 9: 123–128.

    Article  CAS  Google Scholar 

  23. Liu T, Liu PY, Marshall GM . The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res 2009; 69: 1702–1705.

    Article  CAS  PubMed  Google Scholar 

  24. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 2007; 67: 6612–6618.

    Article  CAS  Google Scholar 

  25. Lee H, Kim KR, Noh SJ, Park HS, Kwon KS, Park BH et al. Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma. Hum Pathol 2011; 42: 204–213.

    Article  CAS  PubMed  Google Scholar 

  26. Chen J, Zhang B, Wong N, Lo AW, To KF, Chan AW et al. Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. Cancer Res 2011; 71: 4138–4149.

    Article  CAS  PubMed  Google Scholar 

  27. Holloway KR, Barbieri A, Malyarchuk S, Saxena M, Nedeljkovic-Kurepa A, Cameron MM et al. SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression. Mol Endocrinol 2013; 27: 480–490.

    Article  CAS  PubMed  Google Scholar 

  28. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E . The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 2003; 11: 437–444.

    Article  CAS  PubMed  Google Scholar 

  29. Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev 2006; 20: 1256–1261.

    Article  CAS  PubMed  Google Scholar 

  30. Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011; 20: 487–499.

    Article  CAS  PubMed  Google Scholar 

  31. Yang MH, Laurent G, Bause AS, Spang R, German N, Haigis MC et al. HDAC6 and SIRT2 Regulate the Acetylation State and Oncogenic Activity of Mutant K-RAS. Mol Cancer Res 2013; 11: 1072–1077.

    Article  CAS  PubMed  Google Scholar 

  32. Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ 2013; 20: 503–514.

    Article  CAS  PubMed  Google Scholar 

  33. Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J et al. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3beta/beta-catenin signaling. Hepatology 2013; 57: 2287–2298.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang Y, Zhang M, Dong H, Yong S, Li X, Olashaw N et al. Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene 2009; 28: 445–460.

    Article  CAS  PubMed  Google Scholar 

  35. Holloway KR, Calhoun TN, Saxena M, Metoyer CF, Kandler EF, Rivera CA et al. SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling. Proc Natl Acad Sci USA 2010; 107: 9216–9221.

    Article  CAS  PubMed  Google Scholar 

  36. Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 2006; 66: 4368–4377.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao G, Cui J, Zhang JG, Qin Q, Chen Q, Yin T et al. SIRT1 RNAi knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells. Gene Ther 2011; 18: 920–928.

    Article  CAS  PubMed  Google Scholar 

  38. Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene 2012; 31: 4619–4629.

    Article  CAS  PubMed  Google Scholar 

  39. Byles V, Chmilewski LK, Wang J, Zhu L, Forman LW, Faller DV et al. Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int J Biol Sci 2010; 6: 599–612.

    Article  PubMed  Google Scholar 

  40. Hou H, Chen W, Zhao L, Zuo Q, Zhang G, Zhang X et al. Cortactin is associated with tumour progression and poor prognosis in prostate cancer and SIRT2 other than HADC6 may work as facilitator in situ. J Clin Pathol 2012; 65: 1088–1096.

    Article  PubMed  Google Scholar 

  41. Chen W, ten BD, Brown J, Ahn S, Hu LA, Miller WE et al. Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science 2003; 301: 1391–1394.

    Article  CAS  PubMed  Google Scholar 

  42. Eaton S, Wepf R, Simons K . Roles for Rac1 and Cdc42 in planar polarization and hair outgrowth in the wing of Drosophila. J Cell Biol 1996; 135: 1277–1289.

    Article  CAS  PubMed  Google Scholar 

  43. Habas R, Kato Y, He X . Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1. Cell 2001; 107: 843–854.

    Article  CAS  PubMed  Google Scholar 

  44. Napper AD, Hixon J, McDonagh T, Keavey K, Pons JF, Barker J et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 2005; 48: 8045–8054.

    Article  CAS  PubMed  Google Scholar 

  45. Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M et al. Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 2006; 25: 176–185.

    Article  CAS  PubMed  Google Scholar 

  46. Li Y, Xu W, McBurney MW, Longo VD . SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab 2008; 8: 38–48.

    Article  PubMed  Google Scholar 

  47. Barrio-Real L, Kazanietz MG . Rho GEFs and cancer: linking gene expression and metastatic dissemination. Sci Signal 2012; 5: e43.

    Article  Google Scholar 

  48. Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T et al. New nomenclature for chromatin-modifying enzymes. Cell 2007; 131: 633–636.

    Article  CAS  PubMed  Google Scholar 

  49. Hornbeck PV, Kornhauser JM, Tkachev S, Zhang B, Skrzypek E, Murray B et al. PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res 2012; 40 (Database issue): D261–D270.

    Article  CAS  PubMed  Google Scholar 

  50. Pegtel DM, Ellenbroek SI, Mertens AE, van der Kammen RA, de Rooij J, Collard JG . The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Curr Biol 2007; 17: 1623–1634.

    Article  CAS  PubMed  Google Scholar 

  51. Adam L, Vadlamudi RK, McCrea P, Kumar R . Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. J Biol Chem 2001; 276: 28443–28450.

    Article  CAS  PubMed  Google Scholar 

  52. Adams HC III, Chen R, Liu Z, Whitehead IP . Regulation of breast cancer cell motility by T-cell lymphoma invasion and metastasis-inducing protein. Breast Cancer Res 2010; 12: R69.

    Article  PubMed  Google Scholar 

  53. Wang S, Watanabe T, Matsuzawa K, Katsumi A, Kakeno M, Matsui T et al. Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J Cell Biol 2012; 199: 331–345.

    Article  CAS  PubMed  Google Scholar 

  54. Worthylake DK, Rossman KL, Sondek J . Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1. Nature 2000; 408: 682–688.

    Article  CAS  PubMed  Google Scholar 

  55. Arthur WT, Ellerbroek SM, Der CJ, Burridge K, Wennerberg K . XPLN a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. J Biol Chem 2002; 277: 42964–42972.

    Article  CAS  Google Scholar 

  56. Cajanek L, Ganji RS, Henriques-Oliveira C, Theofilopoulos S, Konik P, Bryja V et al. Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons. Mol Cell Biol 2013; 33: 59–70.

    Article  CAS  PubMed  Google Scholar 

  57. North BJ, Verdin E . Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS One 2007; 2: e784.

    Article  PubMed  Google Scholar 

  58. Gysin S, Salt M, Young A, McCormick F . Therapeutic strategies for targeting ras proteins. Genes Cancer 2011; 2: 359–372.

    Article  CAS  PubMed  Google Scholar 

  59. Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC . Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005; 45: 495–528.

    Article  CAS  PubMed  Google Scholar 

  60. Wagner JM, Hackanson B, Lubbert M, Jung M . Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics 2010; 1: 117–136.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Channing Der at University of North Carolina and Dr Sharon Dent at University of Texas MD Anderson Cancer Center for providing the plasmids. The work described here is funded by a Feist-Weiller Cancer Center Idea Award to KP. MS is supported by the Carroll-Feist Predoctoral Fellowship Award.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, LA, USA

    M Saxena, S Malyarchuk, A E Wang & K Pruitt

  2. Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA

    S S Dykes & J A Cardelli

  3. Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA

    J A Cardelli & K Pruitt

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  1. M Saxena
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Correspondence to K Pruitt.

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Saxena, M., Dykes, S., Malyarchuk, S. et al. The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration. Oncogene 34, 188–198 (2015). https://doi.org/10.1038/onc.2013.549

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