The Yin and Yang of sphingosine kinase 2 (SPHK2): Opposing regulation by nuclear and cytoplasmic localization in lung cancer progression

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator, generated primarily by SPHK1 and SPHK2, regulating cell survival, migration, and angiogenesis. While SPHK1 and SPHK2 have been reported as oncogenes, our prognostic analysis of TCGA-LUAD (Lung Adenocarcinoma) revealed opposite roles for the two enzymes, suggesting a dual function for SPHK2. We investigated the hypothesized tumor suppressor function of SPHK2. Unlike SPHK1, SPHK2 is capable of nuclear localization. Our data showed that high levels of nuclear-localized SPHK2 in tissue correlate with a better prognosis for lung cancer patients. Overexpression of SPHK2 within the nucleus significantly reduced cell proliferation and migration capacity. Furthermore, general SPHK2 overexpression enhanced sensitivity to the drug FTY720, but this sensitivity was reduced when SPHK2 was overexpressed specifically in the nucleus. This suggests that the localization of SPHK2 in the cytoplasm versus the nucleus results in opposing functions. The TCGA-LUAD expression profile likely reflects SPHK2's dominant tumor-suppressor role due to a higher proportion of its expression being nuclear.