Aim: The tumor microenvironment in solid tumors is characterized by extracellular acidosis, which promotes cancer aggressiveness. In osteosarcoma, the most common primary bone cancer, a highly acidic tumor microenvironment is associated with metastasis and poor prognosis, partly due to metabolic rewiring, including changes in lipid pathways such as those involving sphingosine-1-phosphate, a bioactive sphingolipid. Sphingosine-1-phosphate has been previously implicated in histone deacetylase inhibition and gene activation. Here, we investigated whether acidosis induces nuclear sphingosine-1-phosphate accumulation via sphingosine kinase 2, leading to epigenetic activation of oncogenes like FOS in osteosarcoma. Methods: Osteosarcoma spheroids were cultured under neutral or acidic conditions. Histone H3 acetylation was assessed by capillary Western blotting. FOS expression and FOS nuclear localization were analyzed. Sphingosine-1-phosphate's role was addressed through sphingosine kinase 2 silencing and inhibition (ABC294640). Functional effects were measured using colony formation assays. Patient-derived OS tissues (n = 7) were analyzed for correlations between acidity markers (LAMP2, V-ATPase), sphingosine kinase 2, and FOS expression. Results: Acidosis increased both sphingosine kinase 2 mRNA expression after 24 h and histone H3 acetylation, which followed progressive FOS upregulation and nuclear FOS accumulation. Sphingosine kinase 2 inhibition or silencing reduced these effects and impaired clonogenicity. In patient tissues, sphingosine kinase 2 levels correlated with acidosis markers and FOS expression. Conclusions: We identified a novel mechanism where acidosis stimulates both nuclear sphingosine kinase 2 to synthesize sphingosine-1-phosphate and histone H3 acetylation, ultimately leading to FOS transcription. Targeting this axis decreased clonogenesis, underscoring its therapeutic potential in osteosarcoma and potentially other acid-adapted cancers.
Bozzini, N., Cortini, M., Righi, A., Grigoriadis, A.E., Dack, M., Ilieva, E., et al. (2026). Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis. ACTA PHYSIOLOGICA, 242(6), e70214-N/A [10.1111/apha.70214].
Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis
Bozzini, NicolòPrimo
;Cortini, Margherita;Ilieva, Elizabeta;Baldini, Nicola
;Avnet, SofiaUltimo
2026
Abstract
Aim: The tumor microenvironment in solid tumors is characterized by extracellular acidosis, which promotes cancer aggressiveness. In osteosarcoma, the most common primary bone cancer, a highly acidic tumor microenvironment is associated with metastasis and poor prognosis, partly due to metabolic rewiring, including changes in lipid pathways such as those involving sphingosine-1-phosphate, a bioactive sphingolipid. Sphingosine-1-phosphate has been previously implicated in histone deacetylase inhibition and gene activation. Here, we investigated whether acidosis induces nuclear sphingosine-1-phosphate accumulation via sphingosine kinase 2, leading to epigenetic activation of oncogenes like FOS in osteosarcoma. Methods: Osteosarcoma spheroids were cultured under neutral or acidic conditions. Histone H3 acetylation was assessed by capillary Western blotting. FOS expression and FOS nuclear localization were analyzed. Sphingosine-1-phosphate's role was addressed through sphingosine kinase 2 silencing and inhibition (ABC294640). Functional effects were measured using colony formation assays. Patient-derived OS tissues (n = 7) were analyzed for correlations between acidity markers (LAMP2, V-ATPase), sphingosine kinase 2, and FOS expression. Results: Acidosis increased both sphingosine kinase 2 mRNA expression after 24 h and histone H3 acetylation, which followed progressive FOS upregulation and nuclear FOS accumulation. Sphingosine kinase 2 inhibition or silencing reduced these effects and impaired clonogenicity. In patient tissues, sphingosine kinase 2 levels correlated with acidosis markers and FOS expression. Conclusions: We identified a novel mechanism where acidosis stimulates both nuclear sphingosine kinase 2 to synthesize sphingosine-1-phosphate and histone H3 acetylation, ultimately leading to FOS transcription. Targeting this axis decreased clonogenesis, underscoring its therapeutic potential in osteosarcoma and potentially other acid-adapted cancers.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
