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:

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

Oncogene volume 29, pages 105–116 (2010)Cite this article

Abstract

Anaplastic thyroid carcinoma (ATC) is considered one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemotherapy and radiotherapy. Alteration in histone deacetylase (HDAC) activity has been reported in cancer, thus encouraging the development of HDAC inhibitors, whose antitumor action has been shown in both solid and hematological malignancies. However, the molecular basis for their tumor selectivity is unknown. To find an innovative therapy for the treatment of ATCs, we studied the effects of deacetylase inhibitors on thyroid tumorigenesis models. We show that HDACs 1 and 2 are overexpressed in ATCs compared with normal cells or benign tumors and that HDAC inhibitors induce apoptosis selectively in the fully transformed thyroid cells. Our results indicate that these phenomena are mediated by a novel action of HDAC inhibitors that reduces tumor necrosis factor-related apoptosis-inducing ligand protein degradation by affecting the ubiquitin-dependent pathway. Indeed, the combined treatment with HDAC and proteasome inhibitors results in synergistic apoptosis. These results strongly encourage the preclinical application of the combination deacetylase-proteasome inhibitors for the treatment of ATC.

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

Similar content being viewed by others

References

  • Altucci L, Clarke N, Nebbioso A, Scognamiglio A, Gronemeyer H . (2005). Acute myeloid leukemia: therapeutic impact of epigenetic drugs. Int J Biochem Cell Biol 37: 1752–1762.

    Article  CAS  Google Scholar 

  • Altucci L, Rossin A, Raffelsberger W, Reitmair A, Chomienne C, Gronemeyer H . (2001). Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 7: 680–686.

    Article  CAS  Google Scholar 

  • Altucci L, Stunnenberg HG . (2009). Time for epigenetics. Int J Biochem Cell Biol 41: 2–3.

    Article  CAS  Google Scholar 

  • Ashkenazi A . (2002). Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2: 420–430.

    CAS  Google Scholar 

  • Blumenschein Jr GR., Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ, Ricker JL et al (2008). Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs 26: 81–87.

    Article  CAS  Google Scholar 

  • Bontempo P, Mita L, Miceli M, Doto A, Nebbioso A, De Bellis F et al (2007). Feijoa sellowiana derived natural Flavone exerts anti-cancer action displaying HDAC inhibitory activities. Int J Biochem Cell Biol 39: 1902–1914.

    Article  CAS  Google Scholar 

  • Chiappetta G, Ferraro A, Vuttariello E, Monaco M, Galdiero F, De Simone V et al. (2008). HMGA2 mRNA expression correlates with the malignant phenotype in human thyroid neoplasias. Eur J Cancer 44: 1015–1021.

    Article  CAS  Google Scholar 

  • Dai Y, Chen S, Kramer LB, Funk VL, Dent P, Grant S . (2008). Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 14: 549–558.

    Article  CAS  Google Scholar 

  • Duong V, Bret C, Altucci L, Mai A, Duraffourd C, Loubersac J et al (2008). Specific activity of class II histone deacetylases in human breast cancer cells. Mol Cancer Res 6: 1908–1919.

    Article  CAS  Google Scholar 

  • Duvic M, Vu J . (2007). Vorinostat in cutaneous T-cell lymphoma. Drugs Today (Barc) 43: 585–599.

    Article  CAS  Google Scholar 

  • Earel Jr JK., VanOosten RL, Griffith TS . (2006). Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Res 66: 499–507.

    Article  CAS  Google Scholar 

  • Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP . (1993). High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 91: 179–184.

    Article  CAS  Google Scholar 

  • Fiore L, Pollina LE, Fontanini G, Casalone R, Berlingieri MT, Giannini R et al (1997). Cytokine production by a new undifferentiated human thyroid carcinoma cell line, FB-1. J Clin Endocrinol Metab 82: 4094–4100.

    CAS  PubMed  Google Scholar 

  • Fusco A, Berlingieri MT, Di Fiore PP, Portella G, Grieco M, Vecchio G . (1987). One- and two-step transformations of rat thyroid epithelial cells by retroviral oncogenes. Mol Cell Biol 7: 3365–3370.

    Article  CAS  Google Scholar 

  • Gallinari P, Di Marco S, Jones P, Pallaoro M, Steinkuhler C . (2007). HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res 17: 195–211.

    Article  CAS  Google Scholar 

  • Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG et al (2008). Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 111: 1060–1066.

    Article  CAS  Google Scholar 

  • Glaser KB . (2007). HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol 74: 659–671.

    Article  CAS  Google Scholar 

  • Gore L, Rothenberg ML, O'Bryant CL, Schultz MK, Sandler AB, Coffin D et al (2008). A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res 14: 4517–4525.

    Article  CAS  Google Scholar 

  • Hall MA, Cleveland JL . (2007). Clearing the TRAIL for Cancer Therapy. Cancer Cell 12: 4–6.

    Article  CAS  Google Scholar 

  • Hess-Stumpp H, Bracker TU, Henderson D, Politz O . (2007). MS-275, a potent orally available inhibitor of histone deacetylases—the development of an anticancer agent. Int J Biochem Cell Biol 39: 1388–1405.

    Article  CAS  Google Scholar 

  • Iervolino A, Iuliano R, Trapasso F, Viglietto G, Melillo RM, Carlomagno F et al (2006). The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins. Cancer Res 66: 6280–6287.

    Article  CAS  Google Scholar 

  • Inoue S, Mai A, Dyer MJ, Cohen GM . (2006). Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 66: 6785–6792.

    Article  CAS  Google Scholar 

  • Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A et al (2005). Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11: 71–76.

    Article  CAS  Google Scholar 

  • Jenuwein T, Allis CD . (2001). Translating the histone code. Science 293: 1074–1080.

    Article  CAS  Google Scholar 

  • Johnstone RW, Frew AJ, Smyth MJ . (2008). The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 8: 782–798.

    Article  CAS  Google Scholar 

  • Kelly WK, Marks PA . (2005). Drug insight: Histone deacetylase inhibitors—development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2: 150–157.

    Article  CAS  Google Scholar 

  • Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T et al (2005). Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23: 3923–3931.

    Article  CAS  Google Scholar 

  • Kummar S, Gutierrez M, Gardner ER, Donovan E, Hwang K, Chung EJ et al (2007). Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res 13: 5411–5417.

    Article  CAS  Google Scholar 

  • Lin Z, Bazzaro M, Wang MC, Chan KC, Peng S, Roden RB . (2009). Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res 15: 570–577.

    Article  CAS  Google Scholar 

  • Macher-Goeppinger S, Aulmann S, Tagscherer KE, Wagener N, Haferkamp A, Penzel R et al (2009). Prognostic value of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors in renal cell cancer. Clin Cancer Res 15: 650–659.

    Article  CAS  Google Scholar 

  • Mahalingam D, Szegezdi E, Keane M, Jong S, Samali A . (2009). TRAIL receptor signalling and modulation: Are we on the right TRAIL? Cancer Treat Rev 35: 280–288.

    Article  CAS  Google Scholar 

  • Mai A, Altucci L . (2009). Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead. Int J Biochem Cell Biol 41: 199–213.

    Article  CAS  Google Scholar 

  • Mai A, Massa S, Pezzi R, Simeoni S, Rotili D, Nebbioso A et al (2005). Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J Med Chem 48: 3344–3353.

    Article  CAS  Google Scholar 

  • Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R . (2007). FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12: 1247–1252.

    Article  CAS  Google Scholar 

  • Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK . (2001). Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1: 194–202.

    Article  CAS  Google Scholar 

  • Marks PA . (2007). Discovery and development of SAHA as an anticancer agent. Oncogene 26: 1351–1356.

    Article  CAS  Google Scholar 

  • Miller CP, Ban K, Dujka ME, McConkey DJ, Munsell M, Palladino M et al (2007). NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110: 267–277.

    Article  CAS  Google Scholar 

  • Miller CP, Rudra S, Keating MJ, Wierda WG, Palladino M, Chandra J . (2009). Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells. Blood 113: 4289–4299.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Mitsiades CS, Poulaki V, McMullan C, Negri J, Fanourakis G, Goudopoulou A et al (2005). Novel histone deacetylase inhibitors in the treatment of thyroid cancer. Clin Cancer Res 11: 3958–3965.

    Article  CAS  Google Scholar 

  • Nappi TC, Salerno P, Zitzelsberger H, Carlomagno F, Salvatore G, Santoro M . (2009). Identification of Polo-like kinase 1 as a potential therapeutic target in anaplastic thyroid carcinoma. Cancer Res 69: 1916–1923.

    Article  CAS  Google Scholar 

  • Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P et al (2005). Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 11: 77–84.

    Article  CAS  Google Scholar 

  • Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F et al (2003). BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 88: 5399–5404.

    Article  CAS  Google Scholar 

  • Pallante P, Berlingieri MT, Troncone G, Kruhoffer M, Orntoft TF, Viglietto G et al (2005). UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas. Br J Cancer 93: 464–471.

    Article  CAS  Google Scholar 

  • Pallante P, Federico A, Berlingieri MT, Bianco M, Ferraro A, Forzati F et al (2008). Loss of the CBX7 gene expression correlates with a highly malignant phenotype in thyroid cancer. Cancer Res 68: 6770–6778.

    Article  CAS  Google Scholar 

  • Portella G, Ferulano G, Santoro M, Grieco M, Fusco A, Vecchio G . (1989). The Kirsten murine sarcoma virus induces rat thyroid carcinomas in vivo. Oncogene 4: 181–188.

    CAS  PubMed  Google Scholar 

  • Saltman B, Singh B, Hedvat CV, Wreesmann VB, Ghossein R . (2006). Patterns of expression of cell cycle/apoptosis genes along the spectrum of thyroid carcinoma progression. Surgery 140: 899–905 discussion 905–6.

    Article  Google Scholar 

  • Scognamiglio A, Nebbioso A, Manzo F, Valente S, Mai A, Altucci L . (2008). HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2. Biochim Biophys Acta 1783: 2030–2038.

    Article  CAS  Google Scholar 

  • Xu WS, Parmigiani RB, Marks PA . (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26: 5541–5552.

    Article  CAS  Google Scholar 

  • Yu C, Friday BB, Yang L, Atadja P, Wigle D, Sarkaria J et al (2008). Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. Neuro Oncol 10: 309–319.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC), and from the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MIUR); EU (LSHC-CT2005-518417; HEALTH-F2-2007-200620; HEALTH-F4-2007-200767; HEALTH-F4-2009-221952) and the NOGEC-Naples Oncogenomic Center. We thank Konstantina Vergadou for revising and editing the article, Mario Berardone for the artwork, and Pollice A for providing some plasmids.

Author information

Authors and Affiliations

  1. Istituto di Endocrinologia ed Oncologia Sperimentale, Naples, Italy

    E Borbone, M T Berlingieri & A Fusco

  2. NOGEC (Naples Oncogenomic Center)-CEINGE, Biotecnologie Avanzate, Napoli, Italy

    E Borbone & A Fusco

  3. SEMM—European School of Molecular Medicine, Naples Site, Italy

    E Borbone & A Fusco

  4. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Naples, Italy

    F De Bellis, A Nebbioso & L Altucci

  5. Experimental Oncology Department National Cancer Institute ‘G. Pascale, Functional Genomic Unit, Naples, Italy

    G Chiappetta

  6. Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci-Bolognetti, ‘La Sapienza’ Università di Roma, Rome, Italy

    A Mai

Authors
  1. E Borbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M T Berlingieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F De Bellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Nebbioso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Chiappetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Altucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to L Altucci or A Fusco.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Borbone, E., Berlingieri, M., De Bellis, F. et al. Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation. Oncogene 29, 105–116 (2010). https://doi.org/10.1038/onc.2009.306

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.306

Keywords

This article is cited by

Search

Advanced search

Quick links