title: Transcriptional regulation of 15-lipoxygenase expression by histone h3 lysine 4 methylation/demethylation.
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.
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden. Cheng.Liu@ki.se
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
authors.forename: Hongya
authors.initials: H
authors.lastname: Han
authors.forename: Yidong
authors.initials: Y
authors.lastname: Fan
authors.forename: Frida
authors.initials: F
authors.lastname: Schain
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Xu
authors.forename: Hans-Erik
authors.initials: HE
authors.lastname: Claesson
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: Jan
authors.initials: J
authors.lastname: Sjöberg
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D005786:Gene Expression Regulation; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050800:STAT6 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D006657:Histones; D050800:STAT6 Transcription Factor; D001093:Arachidonate 15-Lipoxygenase; D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; D008239:Lysine