Acetyl-CoA synthetase 2 nuclear translocation impediment contributes to nickel induced histone hypoacetylation and neurite outgrowth impairment

Histone hypoacetylation is a well-documented phenomenon associated with nickel (Ni) induced toxic effects, including neurotoxicity. However, the mechanism for histone hypoacetylation in Ni exposure remains ambiguous. Recently, acetyl-CoA availability, especially in the nuclear compartment, for histone acetylation dynamics, is emphasized. In the present study, histone hypoacetylation was evaluated in Ni neurotoxicity cell models, where Ni exposure caused neurite outgrowth impairment. The effects of Ni on histone deacetylases (HDACs) and histone acetyltransferases (HATs), combining with the results of energy metabolites analysis, revealed that the distortion on acetyl-CoA availability was involved in Ni-induced histone hypoacetylation. The function of three nuclear acetyl-CoA synthetases was evaluated, while Acetyl-CoA synthetase 2 (ACSS2) nuclear translocation impediment was found in Ni exposure. Promoting ACSS2 nuclear translocation restored Ni-induced H3K9 hypoacetylation and neurites outgrowth impairment. These results indicated that Ni inhibited ACSS2 nuclear translocation to compromise the acetyl-CoA supply for histone acetylation. The impact of Ni on ACSS2 nuclear translocation may provide a new sight into the histone acetylation regulation, suggesting Ni-associated health adverse effects.