Journal article
Sterol regulatory element-binding protein 2 maintains glioblastoma stem cells by keeping the balance between cholesterol biosynthesis and uptake
Neuro-oncology (Charlottesville, Va.), Vol.25(9), pp.1578-1591
09/05/2023
DOI: 10.1093/neuonc/noad060
PMCID: PMC10651206
PMID: 36934350
Abstract
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 receptors. 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. Chromatin immunoprecipitation quantitative real-time PCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptors in GSCs.
Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than in 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 conditions.
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.
Details
- Title: Subtitle
- Sterol regulatory element-binding protein 2 maintains glioblastoma stem cells by keeping the balance between cholesterol biosynthesis and uptake
- Creators
- Danling Gu - Nanjing Medical UniversityFengqi Zhou - Nanjing Medical UniversityHao You - Nanjing Medical UniversityJiancheng Gao - Nanjing Medical UniversityTao Kang - Nanjing Medical UniversityDeobrat Dixit - University of California, San DiegoQiulian Wu - University of Pittsburgh Medical CenterKailin Yang - Cleveland ClinicShusheng Ci - Nanjing Medical UniversityDanyang Shan - Nanjing Medical UniversityXiao Fan - Nanjing Medical UniversityWei Yuan - Yancheng First People's HospitalQian Zhang - Nanjing Medical UniversityChenfei Lu - Nanjing Medical UniversityDaqi Li - Nanjing Medical UniversityNingwei Zhao - China Exposomics Institute, Shanghai, ChinaZhumei Shi - Nanjing Medical UniversityWei Gao - Nanjing Medical UniversityFan Lin - Nanjing Medical UniversityJianghong Man - National Center of Biomedical AnalysisQianghu Wang - Nanjing Medical UniversityXu Qian - Nanjing Medical UniversityStephen C Mack - St. Jude Children's Research HospitalWeiwei Tao - Huazhong Agricultural UniversitySameer Agnihotri - University of Pittsburgh Medical CenterNu Zhang - Sun Yat-sen UniversityYongping You - Jiangsu Province HospitalJeremy N Rich - University of Pittsburgh Medical CenterJunxia Zhang - Nanjing Medical UniversityXiuxing Wang - Nanjing Medical University
- Resource Type
- Journal article
- Publication Details
- Neuro-oncology (Charlottesville, Va.), Vol.25(9), pp.1578-1591
- Publisher
- Oxford University Press (OUP)
- DOI
- 10.1093/neuonc/noad060
- PMID
- 36934350
- PMCID
- PMC10651206
- ISSN
- 1522-8517
- eISSN
- 1523-5866
- Language
- English
- Date published
- 09/05/2023
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696859802771
Metrics
2 Record Views