Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stem cell transplantation

Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma

Leukemia volume 29, pages 1918–1927 (2015)Cite this article

Subjects

Abstract

Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Palumbo A, Anderson K . Multiple myeloma. N Engl J Med 2011; 364: 1046–1060.

    Article  CAS  Google Scholar 

  2. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516–2520.

    Article  CAS  Google Scholar 

  3. Munshi NC, Anderson KC . New strategies in the treatment of multiple myeloma. Clin Cancer Res 2013; 19: 3337–3344.

    Article  CAS  Google Scholar 

  4. Bolden JE, Peart MJ, Johnstone RW . Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769–784.

    Article  CAS  Google Scholar 

  5. Falkenberg KJ, Johnstone RW . Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 2014; 13: 673–691.

    Article  CAS  Google Scholar 

  6. Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 2013; 122: 2331–2337.

    Article  CAS  Google Scholar 

  7. Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013; 14: 1129–1140.

    Article  CAS  Google Scholar 

  8. Gimsing P, Hansen M, Knudsen LM, Knoblauch P, Christensen IJ, Ooi CE et al. A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol 2008; 81: 170–176.

    Article  CAS  Google Scholar 

  9. Harrison SJ, Quach H, Link E, Seymour JF, Ritchie DS, Ruell S et al. A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood 2011; 118: 6274–6283.

    Article  CAS  Google Scholar 

  10. Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012; 119: 2579–2589.

    Article  CAS  Google Scholar 

  11. Vogl DT, Raje N, Hari P, Jones SS, Supko JG, Leone G et al. Phase 1B results of ricolinostat (ACY-1215) combination therapy with bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (MM). Blood 2014; 124: 4764.

    Google Scholar 

  12. Verdin E, Dequiedt F, Kasler HG . Class II histone deacetylases: versatile regulators. Trends Genet 2003; 19: 286–293.

    Article  CAS  Google Scholar 

  13. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009; 325: 834–840.

    Article  CAS  Google Scholar 

  14. Lobera M, Madauss KP, Pohlhaus DT, Wright QG, Trocha M, Schmidt DR et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol 2013; 9: 319–325.

    Article  CAS  Google Scholar 

  15. Yuan Z, Peng L, Radhakrishnan R, Seto E . Histone deacetylase 9 (HDAC9) regulates the functions of the ATDC (TRIM29) protein. J Biol Chem 2010; 285: 39329–39338.

    Article  CAS  Google Scholar 

  16. Sen N, Kumari R, Singh MI, Das S . HDAC5, a key component in temporal regulation of p53-mediated transactivation in response to genotoxic stress. Mol Cell 2013; 52: 406–420.

    Article  CAS  Google Scholar 

  17. Lahm A, Paolini C, Pallaoro M, Nardi MC, Jones P, Neddermann P et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci USA 2007; 104: 17335–17340.

    Article  CAS  Google Scholar 

  18. Martin M, Kettmann R, Dequiedt F . Class IIa histone deacetylases: regulating the regulators. Oncogene 2007; 26: 5450–5467.

    Article  CAS  Google Scholar 

  19. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W et al. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 2002; 9: 45–57.

    Article  CAS  Google Scholar 

  20. Chauchereau A, Mathieu M, de Saintignon J, Ferreira R, Pritchard LL, Mishal Z et al. HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF. Oncogene 2004; 23: 8777–8784.

    Article  CAS  Google Scholar 

  21. Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 2006; 66: 8814–8821.

    Article  CAS  Google Scholar 

  22. Moreno DA, Scrideli CA, Cortez MA, de Paula Queiroz R, Valera ET, da Silva Silveira V et al. Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol 2010; 150: 665–673.

    Article  CAS  Google Scholar 

  23. Milde T, Oehme I, Korshunov A, Kopp-Schneider A, Remke M, Northcott P et al. HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res 2010; 16: 3240–3252.

    Article  CAS  Google Scholar 

  24. Logue SE, Cleary P, Saveljeva S, Samali A . New directions in ER stress-induced cell death. Apoptosis 2013; 18: 537–546.

    Article  Google Scholar 

  25. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6: 1099–1108.

    Article  CAS  Google Scholar 

  26. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003; 11: 619–633.

    Article  CAS  Google Scholar 

  27. Kimball SR, Clemens MJ, Tilleray VJ, Wek RC, Horetsky RL, Jefferson LS . The double-stranded RNA-activated protein kinase PKR is dispensable for regulation of translation initiation in response to either calcium mobilization from the endoplasmic reticulum or essential amino acid starvation. Biochem Biophys Res Commun 2001; 280: 293–300.

    Article  CAS  Google Scholar 

  28. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr ., Lee KP, Boise LH . Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107: 4907–4916.

    Article  CAS  Google Scholar 

  29. Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L et al. Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. Blood 2012; 119: 5772–5781.

    Article  CAS  Google Scholar 

  30. Yang Y, Qin X, Liu S, Li J, Zhu X, Gao T et al. Peroxisome proliferator-activated receptor gamma is inhibited by histone deacetylase 4 in cortical neurons under oxidative stress. J Neurochem 2011; 118: 429–439.

    Article  CAS  Google Scholar 

  31. Zhang P, Sun Q, Zhao C, Ling S, Li Q, Chang YZ et al. HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4. Cell Signal 2014; 26: 556–563.

    Article  CAS  Google Scholar 

  32. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006; 107: 4053–4062.

    Article  CAS  Google Scholar 

  33. Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia 2013; 27: 2366–2375.

    Article  CAS  Google Scholar 

  34. Hideshima T, Chauhan D, Kiziltepe T, Ikeda H, Okawa Y, Podar K et al. Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications. Blood 2009; 113: 5228–5236.

    Article  CAS  Google Scholar 

  35. Lopez-Corral L, Corchete LA, Sarasquete ME, Mateos MV, Garcia-Sanz R, Ferminan E et al. Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies. Haematologica 2014; 99: 1365–1372.

    Article  CAS  Google Scholar 

  36. Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 2007; 109: 3177–3188.

    Article  CAS  Google Scholar 

  37. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 2001; 412: 300–307.

    Article  CAS  Google Scholar 

  38. Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH . Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 2003; 4: 321–329.

    Article  CAS  Google Scholar 

  39. Schroder M, Kaufman RJ . ER stress and the unfolded protein response. Mutat Res 2005; 569: 29–63.

    Article  Google Scholar 

  40. Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007; 129: 1337–1349.

    Article  CAS  Google Scholar 

  41. Tabas I, Ron D . Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011; 13: 184–190.

    Article  CAS  Google Scholar 

  42. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61: 3071–3076.

    CAS  Google Scholar 

  43. Bantscheff M, Hopf C, Savitski MM, Dittmann A, Grandi P, Michon AM et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat Biotechnol 2011; 29: 255–265.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by ITO Foundation for the Promotion of Medical Science (to SK) and the National Institutes of Health (RO-1 CA 178264). KCA is an American Cancer Society Clinical Research Professor.

Author Contributions

SK designed and performed experiments, analyzed the data and prepared the manuscript; RS and HO designed and performed experiments and analyzed the data; YY, DL, FC, JJ, GB, TH, GG, YT and PGR performed experiments; TH and KCA designed experiments, analyzed the data and prepared the manuscript.

Author information

Author notes

  1. S Kikuchi and R Suzuki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    S Kikuchi, R Suzuki, H Ohguchi, Y Yoshida, D Lu, F Cottini, J Jakubikova, G Bianchi, T Harada, G Gorgun, Y-T Tai, P G Richardson, T Hideshima & K C Anderson

Authors
  1. S Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Ohguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F Cottini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Jakubikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Gorgun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y-T Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. P G Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T Hideshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K C Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K C Anderson.

Ethics declarations

Competing interests

PGR is a member of advisory board for Celgene, Millennium, Johnson & Johnson, Novartis and Keryx. TH is a consultant for Acetylon Pharmaceuticals. KCA is a member of advisory board for Millennium, Celgene, Gilead, Bristol Myers Squibb, and Sanofi-Aventis and is a scientific founder of Acetylon and Oncopep. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kikuchi, S., Suzuki, R., Ohguchi, H. et al. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. Leukemia 29, 1918–1927 (2015). https://doi.org/10.1038/leu.2015.83

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.83

This article is cited by

Search

Advanced search

Quick links