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Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells


Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials1,2,3,4,5. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34+ progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.

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Figure 1: MS275 induces proliferation arrest, differentiation and apoptosis of U937 cells.
Figure 2: RNA interference shows that p21 and TRAIL induction are independent activities of MS275
Figure 3: MS275 induces apoptosis and TRAIL expression in the blasts of individuals with AML.


  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Egger, G., Liang, G., Aparicio, A. & Jones, P.A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Vigushin, D.M. & Coombes, R.C. Targeted histone deacetylase inhibition for cancer therapy. Curr. Cancer Drug Targets 4, 205–218 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Minucci, S., Nervi, C., Lo Coco, F. & Pelicci, P.G. Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias? Oncogene 20, 3110–3115 (2001).

    CAS  Article  Google Scholar 

  6. 6

    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 

  7. 7

    Gottlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Phiel, C.J. et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276, 36734–36741 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Amin, H.M., Saeed, S. & Alkan, S. Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17). Br. J. Haematol. 115, 287–297 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Suzuki, T. et al. Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J. Med. Chem. 42, 3001–3003 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Saito, A. et al. A synthetic inhibitor of histone deacetylase, MS-27–275, with marked in vivo antitumor activity against human tumors. Proc. Natl. Acad. Sci. USA 96, 4592–4597 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Rosato, R.R., Almenara, J.A. & Grant, S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res. 63, 3637–3645 (2003).

    CAS  PubMed  Google Scholar 

  13. 13

    Richon, V.M., Sandhoff, T.W., Rifkind, R.A. & Marks, P.A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. USA 97, 10014–10019 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Glaser, K.B. et al. Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol. Cancer Ther. 2, 151–163 (2003).

    CAS  PubMed  Google Scholar 

  15. 15

    Sasakawa, Y. et al. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem. Pharmacol. 64, 1079–1090 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Clarke, N., Jimenez-Lara, A.M., Voltz, E. & Gronemeyer, H. Tumor suppressor IRF-1 mediates retinoid and interferon anticancer signaling to death ligand TRAIL. EMBO J. 23, 3051–3060 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Ammanamanchi, S., Freeman, J.W. & Brattain, M.G. Acetylated sp3 is a transcriptional activator. J. Biol. Chem. 278, 35775–35780 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Bouwman, P. & Philipsen, S. Regulation of the activity of Sp1-related transcription factors. Mol. Cell. Endocrinol. 195, 27–38 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Braun, H., Koop, R., Ertmer, A., Nacht, S. & Suske, G. Transcription factor Sp3 is regulated by acetylation. Nucleic Acids Res. 29, 4994–5000 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis- inducing ligand in vivo. Nat. Med. 5, 157–163 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Litwack, G. (ed.) Vitamins and Hormones: TRAIL, 448 pages (Academic Press, 2004).

    Google Scholar 

  22. 22

    Kelley, S.K. & Ashkenazi, A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr. Opin. Pharmacol. 4, 333–339 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Altucci, L. & Gronemeyer, H. The promise of retinoids to fight against cancer. Nat. Rev. Cancer 1, 181–193 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Altucci, L. et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat. Med. 7, 680–686 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Ryu, H. et al. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc. Natl. Acad. Sci. USA 100, 4281–4286 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Camarero, N., Nadal, A., Barrero, M.J., Haro, D. & Marrero, P.F. Histone deacetylase inhibitors stimulate mitochondrial HMG-CoA synthase gene expression via a promoter proximal Sp1 site. Nucleic Acids Res. 31, 1693–1703 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Won, J., Yim, J. & Kim, T.K. Sp1 and Sp3 recruit histone deacetylase to repress transcription of human telomerase reverse transcriptase (hTERT) promoter in normal human somatic cells. J. Biol. Chem. 277, 38230–38238 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Rosato, R.R., Almenara, J.A., Dai, Y. & Grant, S. Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol. Cancer Ther. 2, 1273–1284 (2003).

    CAS  PubMed  Google Scholar 

  29. 29

    Brummelkamp, T.R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Shiohara, M. et al. Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic proliferation and differentiation in vitro. Blood 93, 2057–2066 (1999).

    CAS  PubMed  Google Scholar 

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This work is dedicated to the memory of T. Battista. We are grateful to C. Erb and J.M. Garnier for modifying the pSUPER vector, a gift of R. Bernards, for permanent RNAi, and construction and validation of the siRNA vectors, E. Wilhelm for ChIP assays, A. Scognamiglio, C. Scafoglio and M. DeSimone for discussions, A. Cuomo and R. Verde for technical assistance. A.N. and N.C. were supported by the European Union, E.V. by a fellowship from the Ministère de la Recherche et Technologie and E.G. by a fellowship from the Ligue Nationale Contre le Cancer. This work was supported by grants from the European Union (QLG1-CT2000-01935 and QLK3-CT2002-02029), Regione Campania, Ministero della Salute R.F. 02/184, Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Istruzione, Università e Ricerca (PRIN 2001067229_002, PRIN 2002067514_002, PRIN 2004D55579 and FIRB RBNE0157EH), the Italian-French GALILEO-VINCI program, Fondation de France, Association for International Cancer Research, Association pour la Recherche sur le Cancer, Université Louis Pasteur, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and Bristol-Myers Squibb.

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Correspondence to Hinrich Gronemeyer or Lucia Altucci.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Three HDAC inhibitors induce TRAIL mRNA and protein expression in different myeloid cell lines. (PDF 32 kb)

Supplementary Fig. 2

Permanent RNA interference to reveal the specific roles of TRAIL and p21, kinetics of differentiation and apoptosis markers, and TRAIL promoter analysis by ChIP assays. (PDF 82 kb)

Supplementary Fig. 3

MS275-induced TRAIL expression precedes differentiation and is responsible for antitumor activity of MS275 in vivo. (PDF 52 kb)

Supplementary Fig. 4

Effect of MS275 exposure on TRAIL mRNA and protein expression in AML patients' blasts and normal CD34+ progenitors. (PDF 27 kb)

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

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