Hedgehog signaling is hampered by inhibition of cholesterol biosynthesis: The GLI1-DNMT1 cooperativity is a critical factor in controlling stemness and EMT in glioblastoma cells.

Abstract

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by therapy resistance, high stemness, and enhanced epithelial-mesenchymal transition (EMT), which contribute to recurrence and metastasis. Cholesterol biosynthesis is essential for GBM cell proliferation and self-renewal, yet its role in regulating tumor plasticity remains poorly understood. Here, we demonstrate that inhibition of cholesterol synthesis by lovastatin suppresses Hedgehog/GLI1 signaling, leading to upregulation of DNMT1. This GLI1-DNMT1 axis mediates reduced EMT, diminished stemness, and enhanced apoptosis in GBM cells. Furthermore, cholesterol supplementation restores the migratory potential as well as enhances stem-like properties of GBM cells. These findings reveal a central role for cholesterol metabolism in GBM progression and highlight the potential of targeting metabolic-epigenetic crosstalk as a therapeutic strategy.

Abstract as supplied by the indexing source. © the authors / publisher.