The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells.
Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors have emerged recently as promising chemotherapeutic agents. One such agent, suberoylanilide hydroxamic acid, is a potent inhibitor of HDACs that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. Because of its low toxicity, suberoylanilide hydroxamic acid is currently in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of <2% of genes in cultured cells. In this study, we show that low micromolar concentrations of suberoylanilide hydroxamic acid induce the expression of 15-lipoxygenase-1 in human colorectal cancer cells. The expression of 15-lipoxygenase-1 correlates with suberoylanilide hydroxamic acid-induced increase in 13-S-hydroxyoctadecadienoic acid levels, growth inhibition, differentiation, and apoptosis observed with these cells. Furthermore, specific inhibition of 15-lipoxygenase-1 significantly reduced the suberoylanilide hydroxamic acid-induced effects. These novel findings are the first demonstration of a mechanistic link between the induction of 15-lipoxygenase-1 by a HDAC inhibitor and apoptosis in cancer cells. This result has important implications for the study of suberoylanilide hydroxamic acid and other HDAC inhibitors in the prevention and therapy of colorectal cancer and supports future investigations of the mechanisms by which HDAC inhibitors up-regulate 15-lipoxygenase-1.
Hsi
Linda C
LC
Department of Clinical Cancer Prevention, Gastrointestinal Medical Oncology, and Division of Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Xi
Xiaopei
X
Lotan
Reuben
R
Shureiqi
Imad
I
Lippman
Scott M
SM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008041:Linoleic Acids / Q000096:biosynthesis; D000077337:Vorinostat
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008041:Linoleic Acids; C024348:13-hydroxy-9,11-octadecadienoic acid; D000077337:Vorinostat; D001093:Arachidonate 15-Lipoxygenase