Expression of 15-lipoxygenase-1 is regulated by histone acetylation in human colorectal carcinoma

Abstract

15-Lipoxygenase-1 (15-LO-1) is expressed at higher levels in human colorectal tumors compared with normal tissue. 15-LO-1 is expressed in cultured human colorectal cells, but only after treatment with sodium butyrate (NaBT), which also stimulates apoptosis and cell differentiation. We examined the regulation of 15-LO-1 in human tissue and the colorectal carcinoma cell lines Caco-2 and SW-480 by treatment with histone deacetylase (HDAC) inhibitors: NaBT, trichostatin A (TSA) and HC toxin. Northern and western analysis showed that expression of 15-LO-1 was up-regulated by these HDAC inhibitors. Furthermore, HDAC inhibitors stimulated promoter activity of the 15-LO-1 gene approximately 12-to 21-fold using the -331/-23 region of the 15-LO-1 promoter, as measured with a luciferase-15-LO-1 promoter-reporter system, suggesting that 15-LO-1 is regulated at the transcriptional level by HDAC inhibitors. Histone proteins in colorectal cells were acetylated after treatment with HDAC inhibitors. Histone acetylation was also measured in human colorectal tissue and a correlation was observed between increased histone acetylation and 15-LO-1 expression. Thus, regulation of 15-LO-1 expression in colorectal tissues appears to occur by a novel and new mechanism associated with histone acetylation. Moreover, these results suggest that 15-LO-1 is a marker that reflects histone acetylation in colorectal carcinoma.

The 5-Lipoxygenase Promoter Is Regulated by DNA Methylation

“…Concerning 5-LO, inhibition of histone deacetylases by trichostatin A (at 330 nM) did not lead to activation of 5-LO gene expression in U937 and HL-60TB cells, although general cellular histone acetylation by trichostatin A was detectable by AUT-gel electrophoresis (data not shown), suggesting that repression of 5-LO gene expression by DNA methylation does not depend primarily on recruitment of trichostatin A-sensitive histone deacetylases but seems to be mediated by other mechanisms. For 15-lipoxygenase, it has been shown that trichostatin A leads to the up-regulation of 15-LO mRNA expression (28), whereas AdC has no effect (data not shown). Another gene of the leukotriene pathway that is regulated by DNA methylation is the leukotriene B4 receptor BLT1.…”

15-Lipoxygenase-1 Metabolites Down-regulate Peroxisome Proliferator-activated Receptor γ via the MAPK Signaling Pathway

“…This study provided the first evidence that 15-LO-1 is clearly expressed in human colorectal carcinoma cells, and it was subsequently shown that the 15-LO-1 is uniquely regulated by histone acetylation (6). Furthermore, human colon tumors have elevated levels of 15-LO-1 compared with the normal adjacent tissue (7).…”

Overexpression of 15-Lipoxygenase-1 Induces Growth Arrest through Phosphorylation of p53 in Human Colorectal Cancer Cells

“…Neoplastic colonic epithelium treated in vitro with the short-chain fatty acid sodium butyrate can be induced to differentiate and undergo apoptosis associated with up-regulation of 15-LOX-1 (4). This enzyme is uniquely regulated by histone acetylation in colorectal cells with generally greater levels of acetylation in neoplastic versus nonneoplastic tissues (13). Increased 15-LOX-1 expression in tumors and regulation linked to histone acetylation suggest a possible role for 15-LOX-1 in tumor development, but expression in normal mucosal epithelium and induction by butyrate suggest a conflicting antitumorigenic activity in the large intestine.…”