Arsenic Trioxide Promotes Histone H3 Phosphoacetylation at the Chromatin of CASPASE-10 in Acute Promyelocytic Leukemia Cells

Arsenic trioxide (As2O3) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As2O3 is believed to function primarily by promoting apoptosis, but the underlying molecular mechanisms remain largely unknown. In...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-12, Vol.277 (51), p.49504-49510
Main Authors: Li, Ji, Chen, Peili, Sinogeeva, Natasha, Gorospe, Myriam, Wersto, Robert P., Chrest, Francis J., Barnes, Janice, Liu, Yusen
Format: Article
Language:English
Subjects:
Acetylation
Antineoplastic Agents - pharmacology
Apoptosis
Arsenic Trioxide
Arsenicals - pharmacology
Blotting, Northern
Blotting, Western
Caspase 10
Caspases - metabolism
Chromatin - metabolism
DNA, Complementary - metabolism
Dose-Response Relationship, Drug
Enzyme Activation
Histones - metabolism
Humans
Leukemia, Promyelocytic, Acute - enzymology
Leukemia, Promyelocytic, Acute - metabolism
Oligonucleotide Array Sequence Analysis
Oligopeptides - pharmacology
Oxides - pharmacology
Phosphorylation
Polymerase Chain Reaction
Precipitin Tests
Protease Inhibitors - pharmacology
Protein Binding
Serine - metabolism
Time Factors
Tumor Cells, Cultured
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Summary:Arsenic trioxide (As2O3) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As2O3 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 As2O3 in acute promyelocytic leukemia NB4 cells. CASPASE-10 expression was found to be potently induced by As2O3. Accordingly, caspase-10 activity also substantially increased in response to As2O3 treatment. A selective inhibitor of caspase-10, Z-AEVD-FMK, effectively blocked caspase-3 activation and significantly attenuated As2O3-triggered apoptosis. Interestingly, the treatment of NB4 cells with As2O3 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 As2O3 potently enhances histone H3 phosphoacetylation at the CASPASE-10 locus. These results suggest that the effect of As2O3 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M207836200