SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells

Feng Geng; Yaogang Zhong; Huali Su; Etienne Lefai; Shino Magaki; Timothy F Cloughesy; William H Yong; Arnab Chakravarti; Deliang Guo

doi:10.1016/j.celrep.2023.112790

SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells

Cell Rep. 2023 Jul 25;42(7):112790. doi: 10.1016/j.celrep.2023.112790. Epub 2023 Jul 11.

Authors

Feng Geng¹, Yaogang Zhong¹, Huali Su¹, Etienne Lefai², Shino Magaki³, Timothy F Cloughesy⁴, William H Yong⁵, Arnab Chakravarti¹, Deliang Guo⁶

Affiliations

¹ Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
² Human Nutrition Unit, French National Research Institute for Agriculture, Food and Environment, University Clermont Auvergne, 63122 Clermont-Ferrand, France.
³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
⁴ Department of Neurology (Neuro-Oncology), David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
⁵ Department of Pathology and Laboratory Medicine, School of Medicine at University of California, Irvine, CA 92617, USA.
⁶ Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center of Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Electronic address: deliang.guo@osumc.edu.

Abstract

Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.

Keywords: ATG4A; ATG9B; CP: Cancer; CP: Metabolism; LC3B; NPC2; SREBP-1; autophagy; cholesterol homeostasis; cholesteryl esters; glioblastoma; lipid droplets.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Brain Neoplasms* / metabolism
Cholesterol / metabolism
Glioblastoma* / pathology
Homeostasis / physiology
Humans
Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

Sterol Regulatory Element Binding Protein 1
Cholesterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding