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 trials. 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.
Nebbioso
Angela
A
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico Luigi de Crecchio 7, 80138, Napoli, Italy.
Clarke
Nicole
N
Voltz
Emilie
E
Germain
Emmanuelle
E
Ambrosino
Concetta
C
Bontempo
Paola
P
Alvarez
Rosana
R
Schiavone
Ettore M
EM
Ferrara
Felicetto
F
Bresciani
Francesco
F
Weisz
Alessandro
A
de Lera
Angel R
AR
Gronemeyer
Hinrich
H
Altucci
Lucia
L
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53