Inhibition of core histones acetylation by carcinogenic nickel(II).

Nickel, a well-established human carcinogen, was shown to decrease acetylation of histones H4 and H3 in cultured cells. Such a decrease is expected to suppress gene expression. However, nickel is known to not only suppress but also enhance the expression of many genes. So, perhaps, nickel can alter histone acetylation in a more complex way? In a first step of testing this presumption, we examined acetylation status of histones H2A, H2B, H3 and H4, in human (HAE) and rat (NRK) cells exposed to nickel(II) under various conditions. In both cell lines, acetylation of all four histones was down-regulated by nickel(II) in a concentration- and time-dependent manner. Acetylation of histone H2B was suppressed to greater extent than that of the others, with histone H3 being relatively least affected. The analysis of acetylation status of each of the four lysine sites at the N-terminal tail of histone H2B revealed decreases consistent with those observed in the total acetylation patterns, with the K12 and K20 residues being markedly more affected than K5 and K15 residues. Thus, the decrease in acetylation was to some degree site specific. In NRK cells, the observed uniform down-regulation of histone acetylation was consistent with a marked suppression of global gene transcription measured as [3H]-uridine incorporation into mRNA. However, in HAE cells, global RNA expression was transiently increased (in 24 h) before dropping below control after longer exposure (3 days). In conclusion, the effects of Ni(II) on histone acetylation are inhibitory, with their extent depending on the dose and exposure time. This uniform inhibition, however, is not consistently reflected in global RNA expression that in HAE cells may include both increase and decrease of the expression, clearly indicating the involvement of factors other than histone acetylation. The observed effects may contribute to neoplastic transformation of Ni(II)-exposed cells.

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