Studies on the regulation and function of lipoxygenases in Hodgkin lymphoma

<p>Hodgkin lymphoma (HL) is a unique entity among the lymphomas, with a minority of malignant Hodgkin and Reed-Sternberg (H-RS) cells surrounded by a broad range of infiltrating cells. The infiltration of certain inflammatory cells has been reported to predict prognosis of the disease. In HL tumor microenvironment, the primary H-RS cells and those inflammatory cells interact interdependently. The aberrant cytokine production of H-RS cells has been suggested to contribute to this interdependency. However, little is known in terms of the mechanisms involved in the abnormal cytokine secretion by H-RS cells. Previous studies suggested that several pro-inflammatory molecules likely contribute to the aberrant cytokine secretion of HL, including cysteinyl-leukotrienes receptor type I (CysLT1R) and 15-lipoxygenase-1(15-LOX-1) that are highly expressed in primary H-RS cells and cultured HL-derived L1236 cells.</p><p>Previous and present studies in cultured HL cells demonstrate that CysLT1R mediates transcription and secretion of cytokines, including interleukin (IL)-6, IL-8 and tumor necrosis factor-α, upon stimulation by leukotriene D4 (LTD4). This lipid mediator is formed from arachidonic acid through the 5-lipoxygenase (5-LOX) pathway and several types of inflammatory cells surrounding H-RS cells can produce cysteinyl-leukotrienes. To depict the intracellular signaling pathways that bridge the LTD4-CysLT1R ligation to cytokine induction, a mechanistic study was carried out in L1236 cells. The results demonstrated that the transcription factor early growth response (EGR)-1 is involved in the LTD4-triggered cytokine transcriptional induction.</p><p>The regulatory mechanisms implicated in 15-LOX-1 trans-activation in HL have been obscure. This study has also assessed the epigenetic modulation of 15-LOX-1 in different aspects. The results revealed that signal transducer and activator of transcription (STAT)-6 positively regulates 15-LOX-1 transcription by binding to its promoter, in which three putative STAT-6 binding motifs are identified to be required for full activation. The accessibility of STAT-6 to the 15-LOX-1 promoter is controlled by DNA methylation and histone modification. The histone H3 lysine (K)-4 specific methyltransferase SMYD3 was found to exhibit an important role in this multi-step regulation. Although the H3K27me3 demethylase UTX mediates 15-LOX-1 trans-activation by H3K27 demethylation upon IL-4 stimulation in lung carcinoma A549 cells, a crucial histone H3K27-demethylase-independent role of UTX in 15-LOX-1 transcriptional regulation in L1236 cells was demonstrated.</p><p>In conclusion, this study has evaluated the biology of HL by using in vitro models, focusing on lipoxygenases regulation and function. The results not only demonstrated a signaling pathway that hypothetically bridges 5-LOX activity to the striking inflammatory microenvironment in HL, but also uncovered epigenetic regulation mechanisms involved in 15-LOX-1 expression in HL-derived cells. Our findings suggest that lipid signaling pathways might play critical roles in HL pathogenesis, thus warranting further HL research.</p><h3>List of scientific papers</h3><p>I. Han H, Xue-Franzén Y, Miao X, Nagy E, Xu D, Sjöberg J, Björkholm M, Claesson HE. Studies on the signal transduction pathway involved in leukotriene D4-induced release of cytokines from the Hodgkin Lymphoma Cell Line L1236. [Submitted]</p><p>II. Liu C, Xu D, Han H, Fan Y, Schain F, Xu Z, Claesson HE, Björkholm M, Sjöberg J. Transcriptional regulation of 15-lipoxygenase expression by histone h3 lysine 4 methylation/demethylation. PLoS One. 2012; 7(12): p e52703. <br><a href="https://doi.org/10.1371/journal.pone.0052703.">https://doi.org/10.1371/journal.pone.0052703.</a><br><br> </p><p>III. Liu C, Schain F, Han H, Xu D, Andersson-Sand H, Forsell P, Claesson HE, Björkholm M, Sjöberg J. Epigenetic and transcriptional control of the 15-lipoxygenase-1 gene in a Hodgkin lymphoma cell line. Exp Cell Res. 2012; 318(3): p 169-76. <br><a href="https://doi.org/10.1016/j.yexcr.2011.10.017">https://doi.org/10.1016/j.yexcr.2011.10.017</a><br><br> </p><p>IV. Han H, Xu D, Liu C, Claesson HE, Björkholm M, Sjöberg J. Interleukin-4-mediated 15-Lipoxygenase-1 trans-activation depends on UTX recruitment and H3K27Me3 demethylation at the 15-LOX-1 promoter in A549 cells. PLoS One. [Accepted] <br><a href="https://pubmed.ncbi.nlm.nih.gov/24465480">https://pubmed.ncbi.nlm.nih.gov/24465480</a><br><br> </p>