Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC.

ABSTRACT: Cisplatin resistance poses a substantial hurdle in effectively treating head and neck squamous cell carcinoma (HNSCC). Utilizing multiple tumor models and examining an internal HNSCC cohort, squalene epoxidase (SQLE) is pinpointed as a key driver of chemoresistance and tumorigenesis, operating through a cholesterol-dependent pathway. Comprehensive transcriptomic analysis reveals that SQLE is essential for maintaining c-Myc transcriptional activity by stabilizing the c-Myc protein and averting its ubiquitin-mediated degradation. Mechanistic investigation demonstrates that SQLE inhibition diminishes Akt's binding affinity to lipid rafts via a cholesterol-dependent process, subsequently deactivating lipid raft-localized Akt, reducing GSK-3β phosphorylation at S9, and increasing c-Myc phosphor

SUBMITTER: Zhao X 

PROVIDER: S-EPMC10520660 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature