Human 5-lipoxygenase regulates transcription by association to euchromatin

Kreiß, Marius; Oberlis, Julia; Seuter, Sabine; Bischoff-Kont, Iris; Sürün, Duran; Thomas, Dominique; Göbel, Tamara; Schmid, Tobias; Rådmark, Olof; Brandes, Ralf P.; Fürst, Robert; Häfner, Ann-Kathrin; Steinhilber, Dieter

doi:10.1016/j.bcp.2022.115187

Cited by 12 publications

(14 citation statements)

References 97 publications

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“…Also, in normal human prostate cells (NHP) ALOX15B was found to be predominantly localized in the cytosol, while some protein was detected in the nucleus or associated with cytoskeletal proteins, microsomes, and membranes ( Bhatia et al, 2003 ). Localization in the nucleus may suggest a non-enzymatic function of the protein as proposed for other LOX isoforms ( Kreiß et al, 2022 ). Interestingly, alternative splice variants of ALOX15B have not been described to localize to the nucleus ( Bhatia et al, 2003 ) and demonstrated very little AA metabolizing activity ( Tang et al, 2007 ).…”

Section: Structural Organization Of Alox15bmentioning

confidence: 91%

“…How ALOX15B is implicated in the regulation of erythropoiesis is unknown so far, but apart from this, ALOX15B is linked to a variety of pathological states. With Gonzalez et al (2004) and Kilty et al (1999) Lymph node R Kilty et al (1999) Placenta (amnion) Fibroblast R P Zhang et al (2022) Prostate Epithelial Cytoplasmic and nuclear this review, we aim to summarize the existing findings on the enzymatic and biological function of ALOX15B and cast light on its implication in inflammatory diseases and cancer.…”

Section: Introductionmentioning

confidence: 99%

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Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology

2022

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As a lipoxygenase (LOX), arachidonate 15-lipoxygenase type B (ALOX15B) peroxidizes polyenoic fatty acids (PUFAs) including arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid (LA) to their corresponding fatty acid hydroperoxides. Distinctive to ALOX15B, fatty acid oxygenation occurs with positional specificity, catalyzed by the non-heme iron containing active site, and in addition to free PUFAs, membrane-esterified fatty acids serve as substrates for ALOX15B. Like other LOX enzymes, ALOX15B is linked to the formation of specialized pro-resolving lipid mediators (SPMs), and altered expression is apparent in various inflammatory diseases such as asthma, psoriasis, and atherosclerosis. In primary human macrophages, ALOX15B expression is associated with cellular cholesterol homeostasis and is induced by hypoxia. Like in inflammation, the role of ALOX15B in cancer is inconclusive. In prostate and breast carcinomas, ALOX15B is attributed a tumor-suppressive role, whereas in colorectal cancer, ALOX15B expression is associated with a poorer prognosis. As the biological function of ALOX15B remains an open question, this review aims to provide a comprehensive overview of the current state of research related to ALOX15B.

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Section: Structural Organization Of Alox15bmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology

2022

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“…In fact, 5-LO itself, as well as its products LTB4 and LTD4, were already shown to promote the expression of collagens and laminins (365) (366) (367). In Mono Mac 6 cells, knockout of 5-LO was recently shown to increase cell adhesion to human umbilical vein endothelial cells (HUVEC), proving the relevance of this enzyme for said processes (320).…”

Section: Gene Expression Is Cell Line Dependently Altered By 5-lomentioning

confidence: 96%

“…All of those are known to directly and indirectly -via microRNA processing -influence DNA transcription as well as processes like cell viability, adhesion, and motility. Interaction with those partners is a possible explanation for the examined effects but it remains also possible that other unknown, non-canonical mechanisms are involved here (262) (310) (316) (320). A possible explanation for the canonical function and thereby the effects mimicked by inhibiting 5-LO could be that oxygenated lipids produced by 5-LO are integrated into phospholipids of the cell membrane thereby altering membrane fluidity resulting in more static and immobile cells (384).…”

Section: Pharmacological Inhibition Of 5-lo Partly Reproduces the Eff...mentioning

confidence: 99%

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Influence of the CRISPR/Cas mediated knockout of 5-Lipoxygenase on tumour cells

Weißer¹

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This work investigated the influence of the CRISPR/Cas9 mediated knockout of 5-lipoxygenase (5-LO) on different adherent tumour cell lines derived from solid tumours. For this, the 5-LO expressing tumour cell lines HCT-116, HT-29, and U-2 OS were transiently transfected using a plasmid carrying the CRISPR/Cas9 complex sequence to the ALOX5 gene. Subsequently, cells were selected using Puromycin and analysed via Western blotting and DNA Sanger sequencing. Cells that were transfected with a control plasmid missing the guide RNA sequence, were used as a control for all experiments. Differential gene expression analysis, performed after next-generation RNA sequencing, revealed that the expression of various genes was altered after the knockout of 5-LO. In HCT-116 cells, 28 genes were expressed differentially in all 5-LO knockout single-cell clones, while in HT-29 cells the expression of 18 genes and in U-2 OS cells of 234 genes was influenced by the knockout of 5-LO. These findings were validated by real-time qPCR. A lot of the genes that were influenced by the 5-LO knockout are known to be connected to epithelial-mesenchymal-transition (EMT), a process necessary for tumour metastasis. The results from RNA sequencing were the starting point for further investigations. In the following, different aspects of the tumour cell lines were examined. In HT-29, as well as in U-2 OS cells, it was shown that knockout of the 5-LO resulted in impaired cell proliferation. Also, the formation of three-dimensional tumour spheroids was altered. In HT-29 cells, the knockout of 5-LO increased the number of cells in spheroids. In contrast, in U-2 OS cells, the number of cells per spheroid was decreased, even though the diameter of the spheroids was increased, due to more loosely packed spheroids. The difference between 5-LO positive and negative U-2 OS cells became even more obvious after embedding the spheroids in an artificial extracellular matrix. In that scenario, cells lacking the 5-LO formed smaller spheroids that did not have the same ability to grow into the extracellular matrix as 5-LO positive cells did. Also, directed cell migration was strongly influenced by the knockout of 5-LO. In both, HCT-116 and U-2 OS cells, directed cell migration towards a serum gradient was increased in 5-LO knockout single-cell clones. Pharmacological inhibition of the enzyme was used to investigate, whether canonical or non-canonical functions were responsible for the previously mentioned effects. Therefore, vector control cells were treated with the 5-LO inhibitors Zileuton and CJ-13610 in different concentrations. Interestingly, only some of the effects mediated by the complete knockout of 5-LO could be reproduced by inhibiting the enzyme, leading to the suggestion, that canonical, as well as non-canonical functions of 5-LO, play a role in these tumour cells. To conclude, it was shown in this study, that 5-LO affects various cellular functions when expressed in adherent tumour cell lines. These cell line-dependent effects result in altered gene expression, enhanced proliferation, and spheroid formation, as well as impaired cell motility, and can be mediated by enzymatic activity as well as other non-canonical functions.

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Synovial 5‐Lipoxygenase–Derived Oxylipins Define a Lympho‐Myeloid–Enriched Synovium

Murillo‐Saich,

Coras,

Ramirez

et al. 2024

Arthritis & Rheumatology

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ObjectiveOxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFAs) that modulate inflammation and may remain overexpressed in refractory synovitis. In plasma, they could also be biomarkers of synovial pathology. The aim of this study is to determine if synovial oxylipins in inflamed joints correlate with plasma oxylipins and with synovial histological patterns.MethodsPatients with established rheumatoid or psoriatic arthritis with active disease despite treatment were recruited and paired ST and plasma were collected. Oxylipins were determined by liquid chromatography with tandem mass spectrometry and were classified into groups according to their PUFA precursor and enzyme. The expression of CD20, CD68, CD3 and CD138 was obtained to describe synovial histology. Cell specific expression of oxylipin‐related genes were identified by examining available synovial scRNA‐seq data.ResultsWe included a total of 32 ST and 26 paired‐plasma samples. A total of 71 oxylipins were identified in ST but only 24 were identified in plasma. Only levels of 9,10‐diHOME and tetranor‐PGFM had a significant positive correlation between plasma and ST. Several oxylipins and oxylipin‐related genes were differentially expressed among synovial phenotypes. Specifically, several 5‐LOX‐derived oxylipins were statistically elevated in the lympho‐myeloid phenotype, and associated with B cell expression in RA samples.ConclusionThe lack of correlation between ST and plasma oxylipins suggests that synovial tissue lipid profiling better characterizes active pathways in treated joints. Synovial 5‐LOX‐derived oxylipins were highly expressed in lympho‐myeloid‐enriched synovium. Combination therapy with 5‐LOX inhibitors to improve refractory inflammation may be needed in patients with this histological group.

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Human 5-lipoxygenase regulates transcription by association to euchromatin

Cited by 12 publications

References 97 publications

Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology

Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology

Influence of the CRISPR/Cas mediated knockout of 5-Lipoxygenase on tumour cells

Synovial 5‐Lipoxygenase–Derived Oxylipins Define a Lympho‐Myeloid–Enriched Synovium

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