Histone deacetylase inhibitors (HDI) cause DNA damage in leukemia cells: a mechanism for leukemia-specific HDI-dependent apoptosis?
Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events determine the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis.
Gaymes
Terry J
TJ
Department of Haematological Medicine, Leukemia Sciences Laboratories, The Rayne Institute, GKT School of Medicine, Denmark Hill campus, London, United Kingdom.
Padua
Rose Ann
RA
Pla
Marika
M
Orr
Stephen
S
Omidvar
Nader
N
Chomienne
Christine
C
Mufti
Ghulam J
GJ
Rassool
Feyruz V
FV
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D002087:Butyrates / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005720:Gamma Rays; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D002087:Butyrates; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; D025521:Tumor Suppressor Proteins; C102351:apicidin; C012589:trichostatin A; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine