Abstract
15-Lipoxygenase-1 (15-LOX-1) oxidizes polyunsaturated fatty acids to a rich spectrum of biologically active metabolites and is implicated in physiological membrane remodelling, inflammation and apoptosis. Its deregulation is involved in the pathogenesis of diverse cancer and immune diseases. Recent experimental evidence reveals that dynamic histone methylation/demethylation mediated by histone methyltransferases and demethylases plays a critical role in regulation of chromatin remodelling and gene expression. In the present study, we compared the histone 3 lysine 4 (H3-K4) methylation status of the 15-LOX-1 promoter region of the two Hodgkin lymphoma (HL) cell lines L1236 and L428 with abundant and undetectable 15-LOX-1 expression, respectively. We identified a potential role of H3-K4 methylation in positive regulation of 15-LOX-1 transcription. Furthermore, we found that histone methyltransferase SMYD3 inhibition reduced 15-LOX-1 expression by decreasing promoter activity in L1236 cells. SMYD3 knock down in these cells abolished di−/trimethylation of H3-K4, attenuated the occupancy by the transactivator STAT6, and led to diminished histone H3 acetylation at the 15-LOX-1 promoter. In contrast, inhibition of SMCX, a JmjC-domain-containing H3-K4 tri-demethylase, upregulated 15-LOX-1 expression through induction of H3-K4 trimethylation, histone acetylation and STAT6 recruitment at the 15-LOX-1 promoter in L428 cells. In addition, we observed strong SMYD3 expression in the prostate cancer cell line LNCaP and its inhibition led to decreased 15-LOX-1 expression. Taken together, our data suggest that regulation of histone methylation/demethylation at the 15-LOX-1 promoter is important in 15-LOX-1 expression.
Highlights
Histone H3 acetylation is positively correlated with 15-LOX-1 gene expression in cultured Hodgkin lymphoma (HL) cells [17]; different lines of experimental evidence suggest that H3-K4 trimethylation is mostly associated with active gene expression [32]
The results suggest an association of 15-LOX-1 promoter histone methylation status with transcriptional status of the gene in cultured HL cells
The genomic histone methylation/demethylation regulation mediated by the dynamic balance of histone methyltransferases (HMTs)/HDMs is a common event which is involved in as diverse cellular biological processes as gene transcription, Xchromosome inactivation, DNA damage repair, telomere function and DNA recombination [36]
Summary
15-LOX-1 is a peroxidase which catalyzes the oxygenation of free or membrane-bound polyunsaturated fatty acids containing at least one bis-allylic methylene [1]. It was recently reported that hypermethylation of specific CpG di-nucleotides in the 15LOX-1 promoter leads to the upregulation of 15-LOX-1 expression and enzyme activity in prostate cancer cells [20]. Recent work on colorectal cancer showed that 15-LOX1 promoter methylation levels did not significantly correlate with 15-LOX-1 mRNA expression levels in neither cancer cell lines nor in the patients’ tumor specimens [21]. Additional epigenetic mechanism(s) could be involved in the transcriptional regulation of 15-LOX-1, controlling the tissue- and cell-type specific 15-LOX-1 gene expression. Histone 3 lysine 4 (H3-K4) tri- and di- methylation have an activating effect on gene expression [22]. Evidence supporting a close correlation between promoter histone methylation/demethylation status and 15-LOX-1 gene transcription is presented
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