A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension

Swati Dabral, Christian Muecke, Chanil Valasarajan, Mario Schmoranzer, Astrid Wietelmann, Gregg L. Semenza, Michael Meister, Thomas Muley, Tamina Seeger-Nukpezah, Christos Samakovlis, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Rajkumar Savai, Soni S. Pullamsetti

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Abstract

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 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, 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-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.

Original languageEnglish (US)
Article number2130
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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. (2019). A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nature communications, 10(1), [2130]. https://doi.org/10.1038/s41467-019-10044-z