Histone deacetylase 1: a target of 9-hydroxystearic acid in the inhibition of cell growth in human colon cancer.
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.
Calonghi
Natalia
N
Department of Biochemistry G. Moruzzi, University of Bologna, Bologna, Italy. natalia.calonghi@unibo.it
Cappadone
Concettina
C
Pagnotta
Eleonora
E
Boga
Carla
C
Bertucci
Carlo
C
Fiori
Jessica
J
Tasco
Gianluca
G
Casadio
Rita
R
Masotti
Lanfranco
L
D000107:Acetylation; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D013229:Stearic Acids / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008024:Ligands; D013229:Stearic Acids; C070375:9-hydroxystearic acid; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1