Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

Abstract

Recently, increasing attention has been paid to the role of Squalene epoxidase (SQLE) in several types of cancers. However, its functional role in tumor progression of head and neck squamous cell carcinoma (HNSCC) is still unclear. We performed bioinformatic analyses and relative experiments to assess the potential mechanism of SQLE-mediated HNSCC malignancy. And the results showed that SQLE was significantly upregulated in tumor samples compared with peritumor samples. Mechanistically, miR-584-5p downregulation may lead to the upregulation of SQLE in HNSCC. Moreover, high SQLE expression in HNSCC was associated with TNM stage, distant metastasis, and poor survival, indicating that SQLE be involved in the progression of HNSCC. Furtherly, SQLE boosted proliferation, migration, invasion of HNSCC cells in vitro and in vivo. Bioinformatic studies showed that PI3K/Akt signaling participated in HNSCC progression mediated by SQLE overexpression, which is confirmed by in vitro and in vivo analysis. Particularly, treatment with terbinafine, an inhibitor of SQLE widely used in the treatment of fungal infections, showed a therapeutic influence on HNSCC. Our findings demonstrate that SQLE plays a vital role in HNSCC progression, providing research evidence for SQLE as a prospective HNSCC therapeutic target and for terbinafine as a candidate drug of HNSCC treatment in the future

Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC

“…Recent evidence has indicated that terbinafine may also exhibit potential anticancer properties. [ 34 ] Subsequently, we examined the efficacy of pharmacologically targeting SQLE on cisplatin response in an orthotopic mouse model and a PDX mouse model. The study design schematic is illustrated in Figure 8k .…”

The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies

“…In addition, HMGCR inhibitor simvastatin could also robustly enhances cancer vaccinations and synergizes with anti-PD-1 antibodies, which shows the broad therapeutic perspectives of drugs targeting cholesterol pathways in combination with other anti-tumor treatments ( 63 ). Apart from HMGCR, squalene monooxygenase (SM, also known as squalene epoxidase) which converts squalene to 2,3(S)-oxidosqualene is deemed as the second rate-limiting enzyme in cholesterol biosynthesis and its increased expression was also found associated with poor prognosis in several tumors like prostate cancer, pancreatic adenocarcinoma (PAAD) and head and neck squamous cell carcinoma (HNSCC) ( 64 – 66 ). While inhibition of SM could lead to the accumulation of squalene which further suppresses SCLC proliferation ( 67 ), and its pharmacological blockage also inhibits the invasion of CRPC ( 68 ).…”

Advances in HPV‐associated tumor management: Therapeutic strategies and emerging insights

“…Squalene epoxidase (SQLE) has been found to be highly expressed in HNSCC, and the SQLE-specific inhibitor Terbinafine shows promise as a candidate drug for clinical treatment. 49 In HNSCC, common variants of DNA repair mutations caused by HPV infection increase the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors exhibit sensitization or synergistic effects with radiotherapy and platinum-based chemotherapy.…”

“…Novel anti‐CTLA‐4 drugs, Tremelimumab and Ipilimumab, have been developed to counteract these co‐inhibitory receptors. Squalene epoxidase (SQLE) has been found to be highly expressed in HNSCC, and the SQLE‐specific inhibitor Terbinafine shows promise as a candidate drug for clinical treatment 49 …”