The role of human 5-Lipoxygenase (5-LO) in carcinogenesis - a question of canonical and non-canonical functions. Oncogene 5-Lipoxygenase (5-LO), a fatty acid oxygenase, is the central enzyme in leukotriene (LT) biosynthesis, potent arachidonic acid-derived lipid mediators released by innate immune cells, that control inflammatory and allergic responses. In addition, through interaction with 12- and 15-lipoxgenases, the enzyme is involved in the formation of omega-3 fatty acid-based oxylipins, which are thought to be involved in the resolution of inflammation. The expression of 5-LO is frequently deregulated in solid and liquid tumors, and there is strong evidence that the enzyme plays an important role in carcinogenesis. However, global inhibition of LT formation and signaling has not yet shown the desired success in clinical trials. Curiously, the release of 5-LO-derived lipid mediators from tumor cells is often low, and the exact mechanism by which 5-LO influences tumor cell function is poorly understood. Recent data now show that in addition to releasing oxylipins, 5-LO can also influence gene expression in a lipid mediator-independent manner. These non-canonical functions, including modulation of miRNA processing and transcription factor shuttling, most likely influence cancer cell function and the tumor microenvironment and might explain the low clinical efficacy of pharmacological strategies that previously only targeted oxylipin formation and signaling by 5-LO. This review summarizes the canonical and non-canonical functions of 5-LO with a particular focus on tumorigenesis, highlights unresolved issues, and suggests future research directions. 10.1038/s41388-024-03016-1

Human 5-lipoxygenase regulates transcription by association to euchromatin. Biochemical pharmacology Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, besides its canonical function as an arachidonic acid metabolizing enzyme, is a regulator of gene expression associated with euchromatin. By Crispr-Cas9-mediated 5-LO knockout (KO) in MonoMac6 (MM6) cells and subsequent RNA-Seq analysis, we identified 5-LO regulated genes which could be clustered to immune/defense response, cell adhesion, transcription and growth/developmental processes. Analysis of differentially expressed genes identified cyclooxygenase-2 (COX2, PTGS2) and kynureninase (KYNU) as strongly regulated 5-LO target genes. 5-LO knockout affected MM6 cell adhesion and tryptophan metabolism via inhibition of the degradation of the immunoregulator kynurenine. By subsequent FAIRE-Seq and 5-LO ChIP-Seq analyses, we found an association of 5-LO with euchromatin, with prominent 5-LO binding to promoter regions in actively transcribed genes. By enrichment analysis of the ChIP-Seq results, we identified potential 5-LO interaction partners. Furthermore, 5-LO ChIP-Seq peaks resemble patterns of H3K27ac histone marks, suggesting that 5-LO recruitment mainly takes place at acetylated histones. In summary, we demonstrate a noncanonical function of 5-LO as transcriptional regulator in monocytic cells. 10.1016/j.bcp.2022.115187

Interrelationship between the 5-lipoxygenase pathway and microbial dysbiosis in the progression of Alzheimer's disease. Biochimica et biophysica acta. Molecular and cell biology of lipids Alzheimer's disease (AD) is an age-related neurodegenerative disorder involving neurofibrillary tangles and amyloid plaques. The tau phosphorylation responsible for neurofibrillary tangles and amyloid deposition which causes plaques are both accelerated through the activity of 5-lipoxygenase (5-LO). In addition to these pathological pathways, 5-LO has also been linked to the neuro-inflammation associated with disease progression as well as to dysbiosis in the gut. Interestingly, gut dysbiosis itself has been correlated to AD development. Not only do gut metabolites have direct effects on the brain, but pro-inflammatory mediators such as LPS, BMAA and bacterial amyloids produced in the gut due to dysbiosis reach the brain causing increased neuro-inflammation. While microbial dysbiosis and 5-LO exert detrimental effects in the brain, the cause/effect relationship between these factors remain unknown. These issues may be addressed using mouse models of AD in the context of different knockout mice in the 5-LO pathway in specific pathogen-free, germ-free as well as gnotobiotic conditions. 10.1016/j.bbalip.2021.158982