Abstract
Recent studies have shown that an endogenous lipoperoxidation product, 9-hydroxystearic acid (9-HSA), acts in colon carcinoma cells (HT29) as a growth inhibitor by inducing p21(WAF1) in an immediate-early, p53-independent manner and that p21(WAF1) is required for 9-HSA-mediated growth arrest in HT29 cells. It is conceivable, therefore, to hypothesize that the cytostatic effect induced by this agent is at least partially associated with a molecular mechanism that involves histone deacetylase 1 (HDAC1) inhibition, as demonstrated for sodium butyrate and other specific inhibitors, such as trichostatin A and hydroxamic acids. Here, we show that, after administration, 9-HSA causes an accumulation of hyperacetylated histones and strongly inhibits the activity of HDAC1. The interaction of 9-HSA with the catalytic site of the enzyme has been highlighted by computational modeling of the human HDAC1, using its homolog from the hyperthermophilic Aquifex aeolicus as a template. Consistent with the experimental data, we find that 9-HSA can bind to the active site of the protein, showing that the inhibition of the enzyme can be explained at the molecular level by the ligand-protein interaction.
Highlights
Recent studies have shown that an endogenous lipoperoxidation product, 9-hydroxystearic acid (9-HSA), acts in colon carcinoma cells (HT29) as a growth inhibitor by inducing p21WAF1 in an immediate-early, p53-independent manner and that p21WAF1 is required for 9-HSA-mediated growth arrest in HT29 cells
The expression of the cell cycle kinase inhibitor p21WAF1 is induced in neoplastic cells by histone deacetylase 1 (HDAC1) inhibitors such as phenyl butyrate, sodium butyrate, trichostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA)
The y axis units are expressed as nanomoles of 9-hydroxystearic acid (9-HSA-d) per 106 cells. 9-HSA-d nuclear concentration reached a maximum at 6 h and declined below the limit of detection at 48 h
Summary
Recent studies have shown that an endogenous lipoperoxidation product, 9-hydroxystearic acid (9-HSA), acts in colon carcinoma cells (HT29) as a growth inhibitor by inducing p21WAF1 in an immediate-early, p53-independent manner and that p21WAF1 is required for 9-HSA-mediated growth arrest in HT29 cells It is conceivable, to hypothesize that the cytostatic effect induced by this agent is at least partially associated with a molecular mechanism that involves histone deacetylase 1 (HDAC1) inhibition, as demonstrated for sodium butyrate and other specific inhibitors, such as trichostatin A and hydroxamic acids. Short-chain fatty acids, such as phenyl butyrate and phenyl acetate, inhibit HDAC activity and affect the expression of numerous genes with disparate cellular functions [6,7,8] These agents have been tested in the clinic, but they suffer from a short plasma half-life as well as from the relatively high (millimolar) concentrations that are required for their action. We have investigated whether the effects of 9-HSA on the proliferation of HT29 cells can be related to the inhibition of HDAC1 through a direct ligand-enzyme interaction
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