Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptor. Here, we investigate adaptive behavior of GSCs under different cholesterol supplies.
In silico analysis of patient tumors demonstrated enrichment of cholesterol synthesis associated with decreased angiogenesis. Comparative gene expression of cholesterol biosynthesis enzymes in paired GBM specimens and GSCs were performed. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of SREBP2 on GBM cholesterol biosynthesis, proliferation, and self-renewal. ChIP-qPCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptor in GSCs.
Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than invasive margins. SREBP2 promoted cholesterol biosynthesis in GSCs, especially under starvation, as well as proliferation, self-renewal, and tumor growth. SREBP2 governed the balance between cholesterol biosynthesis and uptake in different nutrient condition.
SREBP2 displays context-specific regulation of cholesterol biology based on its availability in the microenvironment with induction of cholesterol biosynthesis in the tumor core and uptake in the margin, informing a novel treatment strategy for GBM.
Pharmacology, Toxicology and Pharmaceutical Science
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4%
Other
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Unknown
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Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 September 2023.
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#14,589,350
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Outputs from Neuro-Oncology
#1,755
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Outputs of similar age
#179,597
of 406,334 outputs
Outputs of similar age from Neuro-Oncology
#37
of 49 outputs
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