Histone deacetylase 1: a target of 9-hydroxystearic acid in the inhibition of cell growth in human colon cancer.
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| 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.
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| Authors | Natalia Calonghi, Concettina Cappadone, Eleonora Pagnotta, Carla Boga, Carlo Bertucci, Jessica Fiori, Gianluca Tasco, Rita Casadio, Lanfranco Masotti |
| Journal | Journal of lipid research (J Lipid Res) Vol. 46 Issue 8 Pg. 1596-603 (Aug 2005) ISSN: 0022-2275 [Print] United States |
| PMID | 15716589 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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