Arsenic trioxide promotes histone H3 phosphoacetylation at the chromatin of CASPASE-10 in acute promyelocytic leukemia cells.
Arsenic trioxide (As(2)O(3)) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As(2)O(3) is believed to function primarily by promoting apoptosis, but the underlying molecular mechanisms remain largely unknown. In this report, using cDNA arrays, we have examined the changes in gene expression profiles triggered by clinically achievable doses of As(2)O(3) in acute promyelocytic leukemia NB4 cells. CASPASE-10 expression was found to be potently induced by As(2)O(3). Accordingly, caspase-10 activity also substantially increased in response to As(2)O(3) treatment. A selective inhibitor of caspase-10, Z-AEVD-FMK, effectively blocked caspase-3 activation and significantly attenuated As(2)O(3)-triggered apoptosis. Interestingly, the treatment of NB4 cells with As(2)O(3) markedly increased histone H3 phosphorylation at serine 10, an event that is associated with acetylation of the lysine 14 residue. Chromatin immunoprecipitation assays revealed that As(2)O(3) potently enhances histone H3 phosphoacetylation at the CASPASE-10 locus. These results suggest that the effect of As(2)O(3) on histone H3 phosphoacetylation at the CASPASE-10 gene may play an important role in the induction of apoptosis and thus contribute to its therapeutic effects on acute promyelocytic leukemia.
Li
Ji
J
Laboratory of Cellular and Molecular Biology, NIA Intramural Research Program, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Chen
Peili
P
Sinogeeva
Natasha
N
Gorospe
Myriam
M
Wersto
Robert P
RP
Chrest
Francis J
FJ
Barnes
Janice
J
Liu
Yusen
Y
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D053455:Caspase 10; D020169:Caspases / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D002843:Chromatin; D018076:DNA, Complementary; D006657:Histones; D009842:Oligopeptides; D010087:Oxides; D011480:Protease Inhibitors; C470795:benzyloxycarbonyl-alanyl-glutamyl-valyl-aspartic acid fluoromethyl ketone; D012694:Serine; D053455:Caspase 10; D020169:Caspases; C506438:CASP10 protein, human; D000077237:Arsenic Trioxide