Epigenetic Regulation Mediated by Sphingolipids in Cancer

Abstract

Epigenetic changes are heritable modifications that do not directly affect the DNA sequence. In cancer cells, the maintenance of a stable epigenetic profile can be crucial to support survival and proliferation, and said profile can differ significantly from that of healthy cells. The epigenetic profile of a cancer cell can be modulated by several factors, including metabolites. Recently, sphingolipids have emerged as novel modulators of epigenetic changes. Ceramide and sphingosine 1-phosphate have become well known in cancer due to activating anti-tumour and pro-tumour signalling pathways, respectively, and they have recently been shown to also induce several epigenetic modifications connected to cancer growth. Additionally, acellular factors in the tumour microenvironment, such as hypoxia and acidosis, are now recognised as crucial in promoting aggressiveness through several mechanisms, including epigenetic modifications. Here, we review the existing literature on sphingolipids, cancer, and epigenetic changes, with a focus on the interaction between these elements and components of the chemical tumour microenvironment.

Keywords: acidosis; bone cancer; cancer; epigenetics; hypoxia; sphingolipids; tumour microenvironment.

Figure 1

Basic structure of sphingolipids (A) and of the four more studied sphingolipids (B).

Figure 2

Schematic representation of the sphingolipid pathway. Sphingomyelin is converted by sphingomyelinase into ceramide, which then can induce cytochrome C release and increase expression of cathepsin B, CAPK, PP1 and FADD, resulting in cell death. Ceramidase converts ceramide into sphingosine, which can either be reconverted into ceramide via ceramide synthases, or be phosphorylated to S1P by sphingosine kinases. S1P mediates its cell survival effects by interacting with g-protein-coupled receptors S1PR1-5, resulting in activation of several pathways, and by inhibiting HDACs 1 and 2, increasing H3K9 acetylation and upregulating target genes. S1P is cleaved by S1P lyase into Δ2-hexadecenal, which might also be capable of inhibiting HDACs 1 and 2.

Figure 3

Schematic representation of HDAC inhibition by S1P. HDAC1/2 deacetylate histones as part of the Sin3 or NuRD repressor complexes localised at the promoters of target genes. SphK2 binds to said repressor complexes. SphK2 then synthetises S1P that, in turn, binds to and inhibits HDAC1/2, preventing deacetylation and thus increasing overall gene expression.

Figure 4

Schematic representation of the effect of S1P on HIF-1αβ. S1P can bind to the PAS domain of HIF-1α after the latter forms a heterodimer with HIF-1β, resulting in stabilisation of the heterodimer and increased transcription of HIF-1αβ target genes.

Figure 5

Possible mechanisms induced by acidosis in the TME. Extracellular acidosis results from the extrusion of protons in the TME from highly glycolytic cancer cells (1), or by the production of CO₂ from adjacent cells (2). Acidosis, in turn, stimulates sirtuin(s) activity (3) and induces stress in tumour cells, which causes the accumulation of lipids inside the cell, in the form of lipid droplets, (4), and an increase in intracellular S1P (5) and Acetyl-CoA (6). The increased Acetyl-CoA and S1P concentration may lead to inhibition of HDAC1/2 and overexpression of SIRT1, thereby resulting in epigenetic changes.