{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:47:14Z","timestamp":1790286434893,"version":"4.1.0"},"reference-count":77,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["21403"],"award-info":[{"award-number":["21403"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      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\u20101\u2010phosphate, a bioactive sphingolipid. Sphingosine\u20101\u2010phosphate has been previously implicated in histone deacetylase inhibition and gene activation. Here, we investigated whether acidosis induces nuclear sphingosine\u20101\u2010phosphate accumulation via sphingosine kinase 2, leading to epigenetic activation of oncogenes like\n                      <jats:italic>FOS<\/jats:italic>\n                      in osteosarcoma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Osteosarcoma spheroids were cultured under neutral or acidic conditions. Histone H3 acetylation was assessed by capillary Western blotting.\n                      <jats:italic>FOS<\/jats:italic>\n                      expression and FOS nuclear localization were analyzed. Sphingosine\u20101\u2010phosphate's role was addressed through sphingosine kinase 2 silencing and inhibition (ABC294640). Functional effects were measured using colony formation assays. Patient\u2010derived OS tissues (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097) were analyzed for correlations between acidity markers (LAMP2, V\u2010ATPase), sphingosine kinase 2, and\n                      <jats:italic>FOS<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Acidosis increased both sphingosine kinase 2 mRNA expression after 24\u2009h and histone H3 acetylation, which followed progressive\n                      <jats:italic>FOS<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We identified a novel mechanism where acidosis stimulates both nuclear sphingosine kinase 2 to synthesize sphingosine\u20101\u2010phosphate and histone H3 acetylation, ultimately leading to\n                      <jats:italic>FOS<\/jats:italic>\n                      transcription. Targeting this axis decreased clonogenesis, underscoring its therapeutic potential in osteosarcoma and potentially other acid\u2010adapted cancers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70214","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:19:44Z","timestamp":1777263584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sphingosine\u20101\u2010Phosphate Promotes\n                    <scp>FOS<\/scp>\n                    Activation in Osteosarcoma Under Tumor Acidosis"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3951-5233","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Bozzini","sequence":"first","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences University of Bologna  Bologna 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2228-3833","authenticated-orcid":false,"given":"Nicola","family":"Baldini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences University of Bologna  Bologna Italy"},{"name":"Biomedical Science, Technologies, and Nanobiotechnology Lab IRCCS Istituto Ortopedico Rizzoli  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-0591","authenticated-orcid":false,"given":"Sofia","family":"Avnet","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences University of Bologna  Bologna 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