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Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.
Hait, Nitai C; Maiti, Aparna; Xu, Pan; Qi, Qianya; Kawaguchi, Tsutomu; Okano, Maiko; Takabe, Kazuaki; Yan, Li; Luo, Cheng.
Affiliation
  • Hait NC; Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Maiti A; Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Xu P; Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Qi Q; Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Kawaguchi T; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Okano M; School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.
  • Takabe K; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Yan L; Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Luo C; Division of Breast Surgery and Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
FASEB J ; 34(3): 4293-4310, 2020 03.
Article de En | MEDLINE | ID: mdl-32017264
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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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Sphingosine / Lysophospholipides / Noyau de la cellule / Récepteur-1 au facteur croissance endothéliale vasculaire / Récepteur A2B à l'adénosine Type d'étude: Prognostic_studies Limites: Animals / Female / Humans / Pregnancy Langue: En Journal: FASEB J Sujet du journal: BIOLOGIA / FISIOLOGIA Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Sphingosine / Lysophospholipides / Noyau de la cellule / Récepteur-1 au facteur croissance endothéliale vasculaire / Récepteur A2B à l'adénosine Type d'étude: Prognostic_studies Limites: Animals / Female / Humans / Pregnancy Langue: En Journal: FASEB J Sujet du journal: BIOLOGIA / FISIOLOGIA Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique