Direkt zum Inhalt
Merck

Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2020-02-06)
Nitai C Hait, Aparna Maiti, Pan Xu, Qianya Qi, Tsutomu Kawaguchi, Maiko Okano, Kazuaki Takabe, Li Yan, Cheng Luo
ZUSAMMENFASSUNG

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.

MATERIALIEN
Produktnummer
Marke
Produktbeschreibung

Sigma-Aldrich
Monoklonales Anti-β-Aktin in Maus hergestellte Antikörper, clone AC-74, ascites fluid
Avanti
Cer/Sph Mixture II, Avanti Polar Lipids
Avanti
27-hydroxycholesterol (D6), Avanti Polar Lipids LM4114, methanol solution