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 and Soni S. Pullamsetti ()
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Swati Dabral: Max-Planck-Institute for Heart and Lung Research
Christian Muecke: Max-Planck-Institute for Heart and Lung Research
Chanil Valasarajan: Max-Planck-Institute for Heart and Lung Research
Mario Schmoranzer: Max-Planck-Institute for Heart and Lung Research
Astrid Wietelmann: Max-Planck-Institute for Heart and Lung Research
Gregg L. Semenza: Johns Hopkins University School of Medicine
Michael Meister: Thoraxklinik at Heidelberg University Hospital
Thomas Muley: Thoraxklinik at Heidelberg University Hospital
Tamina Seeger-Nukpezah: University of Cologne
Christos Samakovlis: Max-Planck-Institute for Heart and Lung Research
Norbert Weissmann: Justus-Liebig University
Friedrich Grimminger: Justus-Liebig University
Werner Seeger: Max-Planck-Institute for Heart and Lung Research
Rajkumar Savai: Max-Planck-Institute for Heart and Lung Research
Soni S. Pullamsetti: Max-Planck-Institute for Heart and Lung Research

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10044-z

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