Transcriptional Regulation of Sphingosine Kinase 1

Abstract

Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally pro-inflammatory, pro-angiogenic, immunomodulatory, and pro-survival; therefore, high SK1 expression and activity have been associated with certain inflammatory diseases and cancer. It is thus important to develop an understanding of the regulation of SK1 expression and activity. In this review, we explore the current literature on SK1 transcriptional regulation, illustrating a complex system of transcription factors, cytokines, and even micro-RNAs (miRNAs) on the post transcriptional level.

Metabolomic dynamics of the arsenic-transformed bronchial epithelial cells and the derived cancer stem-like cells

“…9) are in great agreement with the most recent human cohort study of Strong Heart Family and untargeted blood metabolomics by Sanchez et al [29] who showed that As 3+ primarily affects fatty acid and lipid metabolism, such as glycerophospholipid and glycosphingolipid, and the methylated form of As 3+ can also perturb energy metabolism in human subjects who were exposed to environmental As 3+ . Several earlier studies also suggested increased expression of the key enzymes in sphingolipid metabolism, such as SPHK1, in human cancers [25], and the direct contribution of the sphingolipid metabolic product, sphingosine-1-p, to the expansion of cancer stem-like cells [26]. Thus, the capacity of As 3+ in rewiring lipid metabolism may play key roles in the carcinogenesis associated with environmental As 3+ exposure.…”

“…A direct contribution of the metabolic product, sphingosine-1-phosphate (sphingosine-1-p), from this pathway to cancer stem cells (CSCs) (Fig. 10a) had also been reported [25,26], which is consistent with the overexpression of sphingosine kinase 1 (SPHK1) in some types of cancer [27]. ChIP-seq analysis revealed that consecutive As 3+ treatment for 24 weeks reduced enrichment of the repressive histone H3 methylation marker H3K9me3 or H3K27me3 on the genes involved in several steps of sphingolipid metabolism (Figs.…”

“…Growing evidence suggests strong association of altered sphingolipid metabolism with human cancer [25]. A direct contribution of the metabolic product, sphingosine-1-phosphate (sphingosine-1-p), from this pathway to cancer stem cells (CSCs) (Fig.…”

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

“…This homeostatic environment is not only regulated by SphKs, the expression and activity of SphKs themselves are also influenced by the homeostatic environment. The activation of SphKs is mediated by three known ways, firstly by phosphorylation of the SphK1 Ser225 site by extracellular regulated protein kinases 1/2 (ERK 1/2), and secondly by external stimuli, especially growth factors and pro-inflammatory factors such as platelet derived growth factor (PDGF), TNF-α, transforming growth factor-β (TGF-β), in addition the activity of SphKs also be increased by up-regulating transcription level ( Kono et al, 2010 ; Bonica et al, 2020 ). When the intracellular and external environments are disrupted by disease occurrence, SphKs are aberrantly activated leading to a disrupted balance of sphingolipid-rheostat ( Figure 1B ).…”

Vitamin D3 Enriches Ceramide Content in Exosomes Released by Embryonic Hippocampal Cells

“…Sphingolipids (SphLs) have long been considered only structural components of cell membranes but in time they have been appreciated as second messengers in a wide array of signaling pathways in cell proliferation, differentiation, senescence, apoptosis and, cancer [11]. The current body of work reveals that VD3 affects SphL metabolism and vice-versa [12].…”