Elsevier

Biochemical Pharmacology

Volume 69, Issue 8, 15 April 2005, Pages 1205-1213
Biochemical Pharmacology

Curcumin-induced histone hypoacetylation: The role of reactive oxygen species

https://doi.org/10.1016/j.bcp.2005.01.014Get rights and content

Abstract

Curcumin (Cur), a well-known dietary pigment derived from Curcuma longa, is a promising anticancer drug, but its in vivo target molecules remain to be clarified. Here we report that exposure of human hepatoma cells to Cur led to a significant decrease of histone acetylation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlling the state of histone acetylation in vivo. Cur treatment resulted in a comparable inhibition of histone acetylation in the absence or presence of trichostatin A (the specific HDAC inhibitor), and showed no effect on the in vitro activity of HDAC. In contrast, the domain negative of p300 (a most potent HAT protein) could block the inhibition of Cur on histone acetylation; and the Cur treatment significantly inhibited the HAT activity both in vivo and in vitro. Thus, it is HAT, but not HDAC that is involved in Cur-induced histone hypoacetylation. At the same time, exposure of cells to low or high concentrations of Cur diminished or enhanced the ROS generation, respectively. And the promotion of ROS was obviously involved in Cur-induced histone hypoacetylation, since Cur-caused histone acetylation and HAT activity decrease could be markedly diminished by the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) or their combination, but not by their heat-inactivated forms. The data presented here prove that HAT is one of the in vivo target molecules of Cur; through inhibiting its activity, Cur induces histone hypoacetylation in vivo, where the ROS generation plays an important role. Considering the critical roles of histone acetylation in eukaryotic gene transcription and the involvement of histone hypoacetylation in the lose of cell viability caused by high concentrations of Cur, these results open a new door for us to further understand the molecular mechanism involved in the in vivo function of Cur.

Section snippets

Materials

Curcumin (Cur), RPMI-1640 medium, trichostatin A (TSA), superoxide dismutase (SOD) and catalase (CAT) were purchased from Sigma. The antibodies recognized histone H3 or H4 acetylated at their N-terminal lysine residues were purchased from Upstate Biotechnology. [3H]-acetate and [3H]-acetyl-CoA were purchased from Amersham. The BCA protein assay kit was purchased from Pierce.

Cell culture and treatment

Human hepatoma Hep3B cells were grown in RPMI-1640 medium with 10% FCS, antibiotics and 5% CO2 at 37 °C. After culturing

Inhibition of Cur on histone acetylation in Hep3B cells

Firstly, effect of Cur on histone acetylation was detected by assaying the incorporation of [3H] acetate in histones in Hep3B cells. At low concentrations (on more than 20 μM), Cur treatment led to no obvious alteration of histone acetylation, while at high concentrations (no less than 25 μM), Cur resulted in a concentration- and time-dependent decrease in histone acetylation (Fig. 1A and B). The inhibition of histone acetylation was sustained for all tested times (24 h). This inhibitory effect of

Discussion

Curcumin is a well-known dietary pigment derived from the plant Curcuma longa. Previous studies indicated that it efficiently induces the proliferation arrest and cell death (including apoptosis and necrosis) in a variety of tumor cells [11], [12], [13], [14], [15], [16], but its in vivo target molecules and anticancer mechanisms remain to be clarified. The present study suggests that inhibition of histone acetylation was one new mechanism for the anticancer activity of Cur, where HAT serves as

Acknowledgements

This project was supported by the National Natural Science Foundation of China, 30400230, the Grant of Lanzhou University, 5715220101, and that from SRF for ROCS, SEM.

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