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 phosphorylation at T58, ultimately leading to c‐Myc destabilization. Importantly, employing an Sqle conditional knockout mouse model, SQLE's critical role in HNSCC initiation and progression is established. The preclinical findings demonstrate the potent synergistic effects of combining terbinafine and cisplatin in arresting tumor growth. These discoveries not only provide novel insights into the underlying mechanisms of SQLE‐mediated cisplatin resistance and tumorigenesis in HNSCC but also propose a promising therapeutic avenue for HNSCC patients unresponsive to conventional cisplatin‐based chemotherapy.

Squalene Epoxidase: Its Regulations and Links with Cancers

“…SQLE was upregulated in tumor tissues compared to normal peritumor tissues and the proliferation phenotype upon SQLE knockdown was also the same as in the previous research [112,117]. In addition, the upregulation of SQLE is associated with cisplatin resistance and the depletion of SQLE can potentiate cisplatin sensitivity in resistant HNSCC cells both in vitro and in vivo [122]. Using a luciferase reporter assay, researchers showed that TCF4 was enriched in the SQLE promoter region and that the β-catenin/TCF4 complex transcriptionally modulated SQLE expression in HNSCC cells upon cisplatin exposure [122].…”

“…In addition, the upregulation of SQLE is associated with cisplatin resistance and the depletion of SQLE can potentiate cisplatin sensitivity in resistant HNSCC cells both in vitro and in vivo [122]. Using a luciferase reporter assay, researchers showed that TCF4 was enriched in the SQLE promoter region and that the β-catenin/TCF4 complex transcriptionally modulated SQLE expression in HNSCC cells upon cisplatin exposure [122]. Furthermore, SQLE inactivation can suppress the global c-Myc transcriptional program in HNSCC cancer stem cells, thereby reducing their stemness and tumorigenic characteristics [122].…”

Identifying squalene epoxidase as a metabolic vulnerability in high‐risk osteosarcoma using an artificial intelligence‐derived prognostic index

“…This synergistic effect echoes a recent report that attributed DDP resistance to SQLE mRNA upregulation, emphasizing that SQLE inhibition can bolster DDP's therapeutic effects in head-and-neck squamous cell carcinoma. 91 These results suggest that, in clinical practice, we can procure biopsy samples from newly diagnosed OSA patients and conduct RNA-seq analysis to elucidate their transcriptomic profiles. Subsequently, we can harmonize these profiles with the meta-OSA cohort and employ our established Shiny app to compute the AIDPI.…”

“…This synergistic effect echoes a recent report that attributed DDP resistance to SQLE mRNA upregulation, emphasizing that SQLE inhibition can bolster DDP's therapeutic effects in head‐and‐neck squamous cell carcinoma. 91 …”

Biodegradable Nanoflowers with Abaloparatide Spatiotemporal Management of Functional Alveolar Bone Regeneration

“…Alveolar bone loss may result from various factors such as periodontal disease, tumor, loss of tooth, aging, and abnormal hormone readiness, etc. Notably, bone absorption occurs in the interstitial defect area after tooth extraction, leading to atrophy of the alveolar bone.…”