Sphingosine Kinase 2 Controls the Aggressive Phenotype of Oral Squamous Cell Carcinoma by Regulating miR-205 and miR-296 through p53

Alterations in micro-RNAs, p53, and sphingolipid metabolism have been associated with head and neck squamous cell carcinoma (HNSCC). However, the role of sphingosine kinase (SK)-2, an enzyme crucial for sphingolipid metabolism, is poorly understood in HNSCC. The aim of this study was to investigate how SK2 and p53 interact to regulate miRNAs miR-205 and miR-296. Analysis of small-RNA sequencing data from nontumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to controls (NOK-Ø) revealed differential expression of >100 miRNAs being half-regulated by p53. The expression of miR-205 was down-regulated, and miR-296 was up-regulated, in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells, while levels were decreased in NOK-SK2 cells with p53 overexpression. Transfection with miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 deregulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor-formation capacity, and NOK-SK2 cells abrogated tumor growth in mice. The results indicate crosstalk between SK2 and p53 in regulating miRNAs 205 and 296, which could be potential therapeutic targets in the treatment of HNSCC.