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

Abstract

Arsenic trioxide (As₂O₃) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-<i>trans</i>-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. <i>CASPASE-10</i> 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 <i>CASPASE-10</i> locus. These results suggest that the effect of As₂O₃ on histone H3 phosphoacetylation at the <i>CASPASE-10</i> gene may play an important role in the induction of apoptosis and thus contribute to its therapeutic effects on acute promyelocytic leukemia.