A RASSF1A-HIF1alpha loop drives Warburg effect in cancer and pulmonary hypertension

Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 alpha (HIF-1alpha) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1alpha, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1alpha forms a feedforward loop driving hypoxia signaling in PH and cancer.

• Dabral, S.
• Muecke, C.
• Valasarajan, C.
• Schmoranzer, M.
• Wietelmann, A.
• Semenza, G. L.
• Meister, M.
• Muley, T.
• Seeger-Nukpezah, T.
• Samakovlis, C.
• Weissmann, N.
• Grimminger, F.
• Seeger, W.
• Savai, R.
• Pullamsetti, S. S.