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.

Keywords

  • Animals
  • *Cell Hypoxia
  • Disease Models, Animal
  • Glycolysis
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hypertension, Pulmonary/*pathology/surgery
  • Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
  • Lung/blood supply/pathology/surgery
  • Lung Neoplasms/*pathology
  • Male
  • Mice
  • Mice, Knockout
  • Myocytes, Smooth Muscle
  • NADPH Oxidase 1/metabolism
  • Primary Cell Culture
  • Promoter Regions, Genetic/genetics
  • Protein Binding
  • Protein Kinase C/metabolism
  • Proteolysis
  • Pulmonary Artery/cytology
  • Signal Transduction
  • Tumor Suppressor Proteins/genetics/*metabolism
Publication details
DOI: 10.1038/s41467-019-10044-z
Journal: Nat Commun
Pages: 2130
Number: 1
Work Type: Original
Access number: 31086178
See publication on PubMed
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