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.

  • Letter
  • Published:

Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway

Nature Medicine volume 11, pages 71–76 (2005)Cite this article

An Erratum to this article was published on 01 February 2005

Abstract

Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer1,2,3,4. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.

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: VPA increases survival of APL mice and induces selective apoptosis of the leukemia blasts.
Figure 2: VPA upregulates TRAIL, DR5, FasL and Fas in APL cells in vivo and in vitro.
Figure 3: Activation of TRAIL and Fas cause VPA-induced APL cell death.
Figure 4: Biological effects of VPA or TSA on non-APL myeloid leukemias.

Similar content being viewed by others

References

  1. Marks, P. et al. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer 1, 194–202 (2001).

    Article  CAS  Google Scholar 

  2. Johnstone, R.W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug Discov. 1, 287–299 (2002).

    Article  CAS  Google Scholar 

  3. Johnstone, R.W. & Licht, J.D. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4, 13–18 (2003).

    Article  CAS  Google Scholar 

  4. Kelly, W.K., O'Connor, O.A. & Marks, P.A. Histone deacetylase inhibitors: from target to clinical trials. Expert Opin. Investig. Drugs 11, 1695–1713 (2002).

    Article  CAS  Google Scholar 

  5. Marks, P.A., Richon, V.M. & Rifkind, R.A. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J. Natl. Cancer Inst. 92, 1210–1216 (2000).

    Article  CAS  Google Scholar 

  6. Grignani, F. et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998).

    Article  CAS  Google Scholar 

  7. Minucci, S. et al. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol. Cell 5, 811–820 (2000).

    Article  CAS  Google Scholar 

  8. Lin, R.J. & Evans, R.M. Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol. Cell 5, 821–830 (2000).

    Article  CAS  Google Scholar 

  9. Minucci, S. et al. PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors. Blood 100, 2989–2995 (2002).

    Article  CAS  Google Scholar 

  10. Melnick, A. & Licht, J.D. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93, 3167–3215 (1999).

    CAS  PubMed  Google Scholar 

  11. Westervelt, P. & Ley, T.J. Seed versus soil: the importance of the target cell for transgenic models of human leukemias. Blood 93, 2143–2148 (1999).

    CAS  PubMed  Google Scholar 

  12. Grignani, F. et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74, 423–431 (1993).

    Article  CAS  Google Scholar 

  13. Ruthardt, M. et al. Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor α (RAR α) and PLZF-RAR α fusion proteins on retinoic acid signalling. Mol. Cell. Biol. 17, 4859–4869 (1997).

    Article  CAS  Google Scholar 

  14. Casini, T. & Pelicci, P.G. A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest. Oncogene 18, 3235–3243 (1999).

    Article  CAS  Google Scholar 

  15. Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002).

    Article  CAS  Google Scholar 

  16. Insinga, A. et al. Impairment of p53 acetylation, stability and function by an oncogenic transcription factor. EMBO J. 23, 1144–1154 (2004).

    Article  CAS  Google Scholar 

  17. Walczak, H. & Krammer, P.H. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp. Cell Res. 256, 58–66 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. LeBlanc, H.N. & Ashkenazi, A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 10, 66–75 (2003).

    Article  CAS  Google Scholar 

  20. Ferrara, F.F. et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res. 61, 2–7 (2001).

    PubMed  Google Scholar 

  21. Johnstone, R.W., Ruefli, A.A. & Lowe, S.W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).

    Article  CAS  Google Scholar 

  22. Westervelt, P. et al. High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARα expression. Blood 102, 1857–1865 (2003).

    Article  CAS  Google Scholar 

  23. Yuan, Y. et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc. Nat.l Acad. Sci. USA 98, 10398–10403 (2001).

    Article  CAS  Google Scholar 

  24. Higuchi, M. et al. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1, 63–74 (2002).

    Article  CAS  Google Scholar 

  25. Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat. Med. 9, 347–351 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Grassilli, M. Faretta, F. Padula, R. Fiorini and D. Croci for discussions. This work was supported by grants from European Community (QLG1-CT-2001-01935), Ministero dell' Istruzione, dell'Universita' e della Ricerca and Associazione Italiana per la Ricerca sul Cancro to P.G.P. and S.M., and from Fondazione Monzino to P.G.P.

Author information

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy

    Alessandra Insinga, Silvia Monestiroli, Simona Ronzoni, Francesco Marchesi, Andrea Viale, Saverio Minucci & Pier Giuseppe Pelicci

  2. IFOM-FIRC Institute, Via Adamello 16, Milan, 20139, Italy

    Silvia Monestiroli, Simona Ronzoni, Francesco Marchesi & Pier Giuseppe Pelicci

  3. San Raffaele Biomedical Science Park of Rome, Via di Castel Romano 100, Rome, 00161, Italy

    Vania Gelmetti & Clara Nervi

  4. Department of Veterinary Pathology, University of Milan, Via Celoria 10, Milan, 20133, Italy

    Francesco Marchesi

  5. Department of Pathology, University of Naples, vico L. De Crecchio 7, Naples, 80138, Italy

    Lucia Altucci

Authors
  1. Alessandra Insinga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Monestiroli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simona Ronzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vania Gelmetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Marchesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Viale
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lucia Altucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Clara Nervi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Saverio Minucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pier Giuseppe Pelicci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Saverio Minucci or Pier Giuseppe Pelicci.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

VPA has no apoptotic effect on normal and preleukemic cells. (PDF 79 kb)

Supplementary Fig. 2

Effects of HDAC-i in vivo and dose-response in vitro. (PDF 125 kb)

Supplementary Fig. 3

VPA induces apoptosis and expression of TRAIL and Fas in blasts from t(15;17) and t(8;21) patients. (PDF 58 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Insinga, A., Monestiroli, S., Ronzoni, S. et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11, 71–76 (2005). https://doi.org/10.1038/nm1160

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1160

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing