Lovastatin Suppresses Stemness and Induces Differentiation in Glioblastoma Stem Cells via DNMT1-Mediated Epigenetic Regulation of Caveolin-1

Abstract

For in vivo characterization of glioblastoma stem cells (GSCs), importance of de novo synthesis of cholesterol in proliferating GSCs is tested. Inhibition of cellular cholesterol biosynthesis by chemical compound, lovastatin; and efflux of membrane cholesterol by MBCyD it was observed that, intracellular biosynthesis inhibition has severe effects on GSCs through downregulation of caveolin-1, stem cell markers CD133, CD44, PAX6 and altered metabolism. CAV1 downregulation in drug-treatment conditions is due to reversal of active epigenetic mark H3K4me3 to H3K4 in the CAV1 promoter region in association with elevated level of KDM5A and DNMT1 due to decrease of HH component Gli1. CAV1 gene knockdown implies that, for maintaining cholesterol homeostasis (synthesis and transport), both signaling and transport activities of caveolin-1 are essential.