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Cited by 41Sphingolipid Metabolism and SignalingCancer, Hypoxia, and MetabolismCancer, Lipids, and Metabolism

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

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Hait, Nitai C., Maiti, Aparna, Xu, Pan, Qi, Qianya, Kawaguchi, Tsutomu, Okano, Maiko, Takabe, Kazuaki, Yan, Li +1 more·2020·The FASEB Journal
DOI 10.1096/fj.201901734rrPMC PMC10112293
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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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Cited by

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Authors
Hait, N. C., Maiti, A., Xu, P., Qi, Q., Kawaguchi, T., Okano, M., Takabe, K., Yan, L., & Luo, C.
Affiliations
  • Roswell Park Comprehensive Cancer Center (US)
  • Chinese Academy of Sciences (CN)
Corresponding author
Hait, Nitai C.
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2020-02-04
Volume
34
Issue
3
Pages
4293-4310
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.201901734rr
PMC
PMC10112293
OpenAlex
W3005263298
Cited by
41
References
8
Citations by year
2026: 8 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 3
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Roswell Park Cancer Institute (714084‐01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
sphingosine-1-phosphate, sphingosine kinase 2, hypoxia-inducible factor-1α, HIF-2α, triple-negative breast cancer, breast cancer metastasis, histone H3 acetylation, vascular endothelial growth factor, PAS domain, transcriptional regulation, therapeutic target
MeSH terms
Acetylation, Adenosine, Animals, Blood Pressure, Cell Nucleus, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Lysophospholipids, Mice, Inbred C57BL, Pregnancy, Sphingosine, Immunoblotting, 5'-Nucleotidase, Vascular Endothelial Growth Factor Receptor-1, Receptor, Adenosine A2B, Epigenesis, Genetic, Mice, Tumor Necrosis Factor Ligand Superfamily Member 14

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