Nature Medicine11, 77 - 84 (2004)
Published online: 26 December 2004; | doi:10.1038/nm1161
Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells
Angela Nebbioso1, Nicole Clarke2, Emilie Voltz2, Emmanuelle Germain2, Concetta Ambrosino1, Paola Bontempo1, Rosana Alvarez3, Ettore M Schiavone4, Felicetto Ferrara4, Francesco Bresciani1, Alessandro Weisz1, Angel R de Lera3, Hinrich Gronemeyer2
& Lucia Altucci1
1
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico Luigi de Crecchio 7, 80138, Napoli, Italy.
2
Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 10142, 67404 Illkirch Cedex, C. U. de Strasbourg, France.
3
Universidade de Vigo, Departamento de Quimica Organica; Facultad de Ciencias, 36200 Vigo, Spain.
4
Ematologia con Trapianto di Cellule Staminali, Ospedale Cardarelli, via Cardarell; 9, 80131, Napoli, Italy.
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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