Studies on the regulation and function of lipoxygenases in Hodgkin lymphoma

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.

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.

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.

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.

List of scientific papers

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]

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.
https://doi.org/10.1371/journal.pone.0052703.

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.
https://doi.org/10.1016/j.yexcr.2011.10.017

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]
https://pubmed.ncbi.nlm.nih.gov/24465480