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

  • 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.

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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.

References

  1. 1

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

  2. 2

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

  3. 3

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

  4. 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).

  5. 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).

  6. 6

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

  7. 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).

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 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).

  13. 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).

  14. 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).

  15. 15

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

  16. 16

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

  17. 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).

  18. 18

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

  19. 19

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

  20. 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).

  21. 21

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

  22. 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).

  23. 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).

  24. 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).

  25. 25

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

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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.

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Correspondence to Saverio Minucci or Pier Giuseppe Pelicci.

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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)

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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

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