Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses of crLXRβ cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms.