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  • Original Article
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Lymphoma

Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy

Abstract

Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-positive DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3Lys685 acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3Tyr705 phosphorylation with minimal effect on STAT3Ser727 and JAK2 tyrosine activity. pSTAT3Tyr705-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3Tyr705-negative DLBCLs. This cytotoxicity was associated with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3Lys685 acetylation but prevented STAT3Tyr705 phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells. These studies provide the rationale for targeting STAT3-positive DLBCL tumors with HDAC inhibitors.

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References

  1. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.

    Article  CAS  PubMed  Google Scholar 

  2. Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM . A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA 2003; 100: 9991–9996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 1937–1947.

    Article  PubMed  Google Scholar 

  4. Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 2011; 29: 200–207.

    Article  PubMed  Google Scholar 

  5. Levy DE, Darnell Jr JE . Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002; 3: 651–662.

    Article  CAS  PubMed  Google Scholar 

  6. Darnell Jr JE . STATs and gene regulation. Science 1997; 277: 1630–1635.

    Article  CAS  PubMed  Google Scholar 

  7. Yang XJ, Seto E . HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 2007; 26: 5310–5318.

    Article  CAS  PubMed  Google Scholar 

  8. Ding BB, Yu JJ, Yu RY, Mendez LM, Shaknovich R, Zhang Y et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 2008; 111: 1515–1523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lam LT, Wright G, Davis RE, Lenz G, Farinha P, Dang L et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood 2008; 111: 3701–3713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yuan ZL, Guan YJ, Chatterjee D, Chin YE . Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 2005; 307: 269–273.

    Article  CAS  PubMed  Google Scholar 

  11. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003; 370 (Part 3): 737–749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Grozinger CM, Schreiber SL . Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol 2002; 9: 3–16.

    Article  CAS  PubMed  Google Scholar 

  13. Bannister AJ, Miska EA, Gorlich D, Kouzarides T . Acetylation of importin-alpha nuclear import factors by CBP/p300. Curr Biol 2000; 10: 467–470.

    Article  CAS  PubMed  Google Scholar 

  14. Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC . NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J 2006; 25: 139–149.

    Article  CAS  PubMed  Google Scholar 

  15. Zhao Y, Lu S, Wu L, Chai G, Wang H, Chen Y et al. Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol 2006; 26: 2782–2790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Catania A, Iavarone C, Carlomagno SM, Chiariello M . Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity. Biochem Biophys Res Commun 2006; 343: 544–554.

    Article  CAS  PubMed  Google Scholar 

  17. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103: 275–282.

    Article  CAS  PubMed  Google Scholar 

  18. Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, Witzig TE . Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood 2009; 114: 2926–2935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Klampfer L, Huang J, Swaby LA, Augenlicht L . Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem 2004; 279: 30358–30368.

    Article  CAS  PubMed  Google Scholar 

  20. Wang H, Holloway MP, Ma L, Cooper ZA, Riolo M, Samkari A et al. Acetylation directs survivin nuclear localization to repress STAT3 oncogenic activity. J Biol Chem 2010; 285: 36129–36137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 1999; 284: 479–482.

    Article  CAS  PubMed  Google Scholar 

  22. Wang R, Cherukuri P, Luo J . Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J Biol Chem 2005; 280: 11528–11534.

    Article  CAS  PubMed  Google Scholar 

  23. O’Shea JJ, Kanno Y, Chen X, Levy DE . Cell signaling. Stat acetylation—a key facet of cytokine signaling? Science 2005; 307: 217–218.

    Article  PubMed  Google Scholar 

  24. Kim DJ, Tremblay ML, Digiovanni J . Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS One 2010; 5: e10290.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zushi S, Shinomura Y, Kiyohara T, Miyazaki Y, Kondo S, Sugimachi M et al. STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer 1998; 78: 326–330.

    Article  CAS  PubMed  Google Scholar 

  26. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10: 105–115.

    Article  CAS  PubMed  Google Scholar 

  27. Lavelle D, Chen YH, Hankewych M, DeSimone J . Histone deacetylase inhibitors increase p21(WAF1) and induce apoptosis of human myeloma cell lines independent of decreased IL-6 receptor expression. Am J Hematol 2001; 68: 170–178.

    Article  CAS  PubMed  Google Scholar 

  28. Ray S, Lee C, Hou T, Boldogh I, Brasier AR . Requirement of histone deacetylase1 (HDAC1) in signal transducer and activator of transcription 3 (STAT3) nucleocytoplasmic distribution. Nucleic Acids Res 2008; 36: 4510–4520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Spurling CC, Godman CA, Noonan EJ, Rasmussen TP, Rosenberg DW, Giardina C . HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol Carcinog 2008; 47: 137–147.

    Article  CAS  PubMed  Google Scholar 

  30. Senese S, Zaragoza K, Minardi S, Muradore I, Ronzoni S, Passafaro A et al. Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol 2007; 27: 4784–4795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Redner RL, Wang J, Liu JM . Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 1999; 94: 417–428.

    CAS  PubMed  Google Scholar 

  32. Li J, Wang J, Nawaz Z, Liu JM, Qin J, Wong J . Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J 2000; 19: 4342–4350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.

    Article  CAS  PubMed  Google Scholar 

  34. McLaughlin F, La Thangue NB . Histone deacetylase inhibitors open new doors in cancer therapy. Biochem Pharmacol 2004; 68: 1139–1144.

    Article  CAS  PubMed  Google Scholar 

  35. Schuringa JJ, Schepers H, Vellenga E, Kruijer W . Ser727-dependent transcriptional activation by association of p300 with STAT3 upon IL-6 stimulation. FEBS Lett 2001; 495: 71–76.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang JJ, Vinkemeier U, Gu W, Chakravarti D, Horvath CM, Darnell Jr JE . Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling. Proc Natl Acad Sci U S A 1996; 93: 15092–15096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bhattacharya S, Schindler C . Regulation of Stat3 nuclear export. J Clin Invest 2003; 111: 553–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kramer OH, Knauer SK, Greiner G, Jandt E, Reichardt S, Guhrs KH et al. A phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev 2009; 23: 223–235.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2006; 12: 4628–4635.

    Article  CAS  PubMed  Google Scholar 

  40. Prince HM, Bishton MJ, Johnstone RW . Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Future Oncol 2009; 5: 601–612.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work is supported by Lymphoma SPORE (P50 CA097274) Career Development Award to MG (from NCI/ University of Iowa/Mayo Clinic); R01CA127433 to TEW and the Predolin Foundation.

Author contributions

MG and TEW designed the research. MG interpreted and analyzed all the data, made the figures and wrote the manuscript. MG, MJS, JJH and LEW performed the experiments. TEW provided clinical samples and wrote the manuscript.

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Correspondence to M Gupta or T E Witzig.

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Gupta, M., Han, J., Stenson, M. et al. Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy. Leukemia 26, 1356–1364 (2012). https://doi.org/10.1038/leu.2011.340

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