Copper induces histone hypoacetylation through directly inhibiting histone acetyltransferase activity.
The abnormal accumulation of Cu2+ is closely correlated with the incidence of different diseases, such as Alzheimer's disease and Wilson disease. To study in vivo functions of Cu2+ will lead to a better understanding of the nature of these diseases. In the present study, effect of Cu2+ on histone acetylation was investigated in human hepatoma cells. Exposure of cells to Cu2+ resulted in a significant decrease of histone acetylation, as indicated by the decrease of the overall histone acetylation and the decrease of histone H3 and H4 acetylation. Since histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlled the state of histone acetylation in vivo, we tested their contribution to the inhibition of Cu2+ on histone acetylation. One hundred nanomolar trichostatin A, the specific inhibitor of HDAC, did not attenuate the inhibitory effect of Cu2+ on histone acetylation. Combined with that Cu2+ showed no effect on the in vitro activity of HDAC, these results led to the conclusion that it is HAT, but not HDAC that is involved in Cu2+ -induced histone hypoacetylation. This conclusion was confirmed by the facts that (1) Cu2+ significantly inhibited the in vitro activity of HAT, (2) Cu2+ -treated cells possessed a lower HAT activity than control cells, and (3) 50 or 100 microM bathocuproine disulfonate, a chelator of Cu2+, significantly attenuated the inhibition of Cu2+ on HAT activity and histone acetylation in the similar pattern. Combined with that Cu2+ showed no or obvious cytotoxicity at 100 or 200 microM in human hepatoma cells, and the previous study that Cu2+ inhibits the histone H4 acetylation of yeast cells at nontoxic or toxic levels, the data presented here suggest that inhibiting histone acetylation is probably one general in vivo function of Cu2+, where HAT is its molecular target.
Kang
Jiuhong
J
School of Life Sciences, Lanzhou University, Gansu 730000, PR China. kangjiuhong@lzu.edu.cn
Lin
Changjun
C
Chen
Jie
J
Liu
Qing
Q
D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology*; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008113:Liver Neoplasms
D006657:Histones; D003300:Copper; D007770:L-Lactate Dehydrogenase; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases