Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis

Area of Science:

• Oncology
• Cancer Biology
• Biochemistry

Background:

• Extracellular acidosis in solid tumors promotes cancer aggressiveness and metastasis.
• In osteosarcoma, acidic microenvironments correlate with poor prognosis, partly due to metabolic rewiring.
• Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid implicated in histone deacetylase inhibition and gene activation.

Purpose of the Study:

• To investigate if acidosis induces nuclear S1P accumulation via sphingosine kinase 2 (SK2).
• To determine if this leads to epigenetic activation of oncogenes, such as FOS, in osteosarcoma.
• To explore the therapeutic potential of targeting the acidosis-SK2-S1P-FOS axis.

Main Methods:

• Osteosarcoma spheroids cultured in neutral vs. acidic conditions.
• Assessed histone H3 acetylation, FOS expression, and nuclear localization.
• Utilized SK2 silencing/inhibition (ABC294640) and colony formation assays.
• Analyzed patient-derived osteosarcoma tissues for correlations between acidity markers, SK2, and FOS.

Main Results:

• Acidosis increased SK2 mRNA expression, histone H3 acetylation, FOS upregulation, and nuclear FOS accumulation.
• SK2 inhibition/silencing reduced these effects and impaired osteosarcoma cell clonogenicity.
• Patient tissues showed correlations between acidosis markers, SK2 levels, and FOS expression.

Conclusions:

• Identified a novel mechanism where acidosis stimulates nuclear SK2, leading to S1P synthesis and histone H3 acetylation.
• This process epigenetically activates FOS transcription, promoting osteosarcoma aggressiveness.
• Targeting the acidosis-SK2-S1P-FOS axis reduced clonogenesis, highlighting its therapeutic potential.