Our previous study demonstrates that copper induces histone hypoacetylation by inhibiting histone acetyltransferase (HAT) activity. However, it lacks direct evidences whether copper-inhibited histone acetylation right contributes to the toxicity of copper. Exposure of human leukemia cells (HL-60) to Cu 2+ resulted in cell proliferation arrest and a concentration- and time-dependent decrease of histone acetylation. At the same time, Cu 2+-induced significant increase of H 2O 2 and O 2 − generation via a concentration- and time-dependent manner too. The histone acetylation was efficiently suppressed by exogenous H 2O 2, and enhanced by superoxide dismutase (the scavenger of O 2 −), catalase (the scavenger of H 2O 2) or the combination of both, indicating that Cu 2+ at least partially inhibited histone acetylation through triggering oxidative stress. Further studies found that sodium butyrate, the inhibitor of histone deacetylase (HDAC), which had no obvious effect on oxidative stress but increased histone acetylation at the concentration of 50 μM, attenuated Cu 2+-inhibited cell proliferation, indicating that histone acetylation inhibition is simultaneously involved in the cytotoxicity of Cu 2+. Considering the important role of histone acetylation in gene transcription and regulation of cell fate, the present study may open a new door to further understand the mechanism of Cu 2+-induced toxicity.
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