Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer

• Published in: Oncogenesis (New York, NY) Vol. 5; no. 3; p. e209
• Main Authors: Bouquerel, P, Gstalder, C, Müller, D, Laurent, J, Brizuela, L, Sabbadini, R A, Malavaud, B, Pyronnet, S, Martineau, Y, Ader, I, Cuvillier, O
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-03-2016; Nature Publishing Group: Open Access Journals - Option C; Nature Publishing Group
• Subjects: 13/106; 38/77; 38/89; 631/67/395; 631/67/589/1588/1351; 82; 96; 96/1; 96/109; 96/95; Apoptosis; Biochemistry; Biochemistry, Molecular Biology; Cell Biology; Chemical Sciences; Human Genetics; Internal Medicine; Life Sciences; Medicine; Medicine & Public Health; Oncology; Organic chemistry; Original; original-article
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/oncsis.2016.13

The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (
V
HL
) gene and expressing high levels of HIF-2α, SphK1 activity controls HIF-2α expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2α loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2α accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P
1
) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2α in diverse cancer cell lineages notably ccRCC, where HIF-2α has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2α expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC.