Dysregulated 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) protect head and neck cancer from Endoplasmic Reticulum stress and apoptotic cell death

ABSTRACT: Altered metabolic pathways that cancer cells reply on for survival and growth are useful targets for therapeutic intervention. Here we show that de novo cholesterol biosynthesis pathways in head and neck squamous cell carcinoma (HNSCC) are highly increased to support tumor survival. Transcriptomics profiling of tumor tissues isolated from patients with HNSCC identified steroid/cholesterol metabolism as the most significantly altered metabolic pathways when compared with paired normal tissues. Disruption of two key enzymes 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) that are elevated and involved in de novo cholesterol biosynthesis using genetic approach or small inhibitory molecules (AY9944 or triparanol) results in increased apoptosis of HNSCC cells despite of replenished cholesterol. Metabolic signatures of cholesterol identified accumulated intracellular 7-dehydrocholesterol (7-DHC), a substrate of DHCR7, when either DHCR7 or DHCR24 is inhibited. Further exogenous 7-DHC supplementation decreased cancer cell viability causing cell death by inducing ER stress through eIF2alpha and IRE1 phosphorylation in HNSCC cells. This study revealed that HNSCC manages ER stresses via elevated cholesterol biosynthesis in order to remove 7-DHC for cancer viability. Our finding suggests that the metabolic intermediates in de novo cholesterol synthesis are metabolic vulnerability of HNSCC to induce ER stress and apoptosis as a potential therapeutic strategy. This study provides the evidence of direct link between the cholesterol metabolism and ER stress for cancer cell viability, suggesting metabolic vulnerability of HNSCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285603 | GEO | 2025/04/01

REPOSITORIES: GEO