ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2020
Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Letter to the Editor: Low-energy fractional carbon dioxide laser priming of mesenchymal stem cell-derived exosomes: A photothermal boost for diabetic wound angiogenesis.World journal of methodology · 2026Article
- Article
- Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis.Acta physiologica (Oxford, England) · 2026Article
- Bioactive Natural Compounds in Triple-Negative Breast Cancer: Molecular Targets and Therapeutic Perspectives.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Lactate: elucidating its indispensable role in human health.Molecular cancer · 2026Review
- BRSK2 plays a role in autophagy and cancer cell growth and survival under nutrient deprivation stress via the PIK3C3 pathway.Scientific reports · 2025Article
- Sphingosine Kinase 2 Regulates Aryl Hydrocarbon Receptor Nuclear Translocation and Target Gene Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Adipocyte sphingosine kinase 1 regulates histone modifiers to disrupt circadian function.bioRxiv : the preprint server for biology · 2024Article
- Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells.Cells · 2024Review
- Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment.Frontiers in immunology · 2024Review
- Screening of functional genes for hypoxia adaptation in Tibetan pigs by combined genome resequencing and transcriptome analysis.Frontiers in veterinary science · 2024Article
- Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension.Circulation research · 2023Article
- Cross-Regulation of the Cellular Redox System, Oxygen, and Sphingolipid Signalling.Metabolites · 2023Review
- Epigenetic Regulation Mediated by Sphingolipids in Cancer.International journal of molecular sciences · 2023Review
- Extracellular sialyltransferase st6gal1 in breast tumor cell growth and invasiveness.Cancer gene therapy · 2022Article
- Article
- Article
- Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells.International journal of molecular sciences · 2022Article
- The function of Sphingosine-1-phosphate receptor 2 (S1PR2) in maintaining intestinal barrier and inducing ulcerative colitis.Bioengineered · 2022Article
- Keep a Little Fire Burning-The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity.International journal of molecular sciences · 2022Review
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Authors and funding
9 authors.
Funding
Abstract
Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine-1-phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia-responsive master transcription factors hypoxia-inducible factor (HIF)-1α/2α, and their functions in breast cancer, with a focus on triple-negative breast cancer (TNBC). We have shown SphK2 is associated with HIF-1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF-1α. SphK2, and HIF-1α expression levels are elevated in metastatic estrogen receptor-positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K-145, that nuclear S1P, histone acetylation, HIF-1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF-1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.
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