Sphingosine kinase 1 is dysregulated via hypoxia-inducible factor 1α in oral squamous cell carcinoma

Background and objectives Hypoxia is the critical hallmark of solid tumours, including oral squamous cell carcinoma (OSCC), which is the most prevalent cancer in the Indian subcontinent. Sphingosine kinase 1 (SphK1) is a known oncogene that is upregulated in most cancers, including OSCC. However, its regulation in the development and progression of OSCC is unknown. The objective of the study was to determine the regulation of SphK1 via hypoxia-inducible factors (HIFs) in OSCC. Methods Tumour and adjacent normal tissues from 70 OSCC patients were collected and snap frozen. Quantitative real-time PCR (qRT-PCR) measured SPHK1, HIF1A, HIF2A expression, and the downstream target of HIF-1α expression. Spearman correlation analysis assessed the association between SPHK1 and HIF1A/HIF2A. Tongue squamous cancer cells, SCC-9 and SCC-25, were treated with CoCl2 or 1% oxygen to induce hypoxia, with or without KC72F (a HIF-1α inhibitor). The SPHK1 promoter was cloned into a pGL3 vector, and luciferase reporter assays were performed in SCC-9 and SCC-25 cells. Stable SphK1 knockdown cells were generated using shRNA. Results HIF1A was overexpressed in 73% of oral squamous cell carcinoma (OSCC) tumours, strongly correlating with SPHK1 expression. Stabilising HIF-1α through CoCl₂ or hypoxia-induced SPHK1 expression was reversed by the HIF-1 inhibitor. The knockdown of SPHK1 in OSCC cells reduced the stability of HIF-2α, but not HIF-1α. Interpretation and conclusion Our study revealed that SPHK1 expression is upregulated through HIF-1α, which in turn stabilises HIF-2α. Thus, inhibition of SphK1 along with HIF-2α might be beneficial for the management of OSCC.