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

Research output: Contribution to journalArticle

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

Fingerprint

hypertension
hypoxia
Pulmonary Hypertension
Hypoxia-Inducible Factor 1
cancer
Association reactions
Neoplasms
Lung Neoplasms
Switches
Hydroxylation
Vascular Diseases
Genetic Promoter Regions
switches
Knockout Mice
knockout mice
Protein Kinase C
Blood Vessels
Phosphorylation
proteins
suppressors

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., ... 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

A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. / Dabral, Swati; Muecke, Christian; Valasarajan, Chanil; Schmoranzer, Mario; Wietelmann, Astrid; Semenza, Gregg L; Meister, Michael; Muley, Thomas; Seeger-Nukpezah, Tamina; Samakovlis, Christos; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Savai, Rajkumar; Pullamsetti, Soni S.

In: Nature communications, Vol. 10, No. 1, 2130, 01.12.2019.

Research output: Contribution to journalArticle

Dabral, S, Muecke, C, Valasarajan, C, Schmoranzer, M, Wietelmann, A, Semenza, GL, Meister, M, Muley, T, Seeger-Nukpezah, T, Samakovlis, C, Weissmann, N, Grimminger, F, Seeger, W, Savai, R & Pullamsetti, SS 2019, 'A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension', Nature communications, vol. 10, no. 1, 2130. https://doi.org/10.1038/s41467-019-10044-z
Dabral, Swati ; Muecke, Christian ; Valasarajan, Chanil ; Schmoranzer, Mario ; Wietelmann, Astrid ; Semenza, Gregg L ; Meister, Michael ; Muley, Thomas ; Seeger-Nukpezah, Tamina ; Samakovlis, Christos ; Weissmann, Norbert ; Grimminger, Friedrich ; Seeger, Werner ; Savai, Rajkumar ; Pullamsetti, Soni S. / A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. In: Nature communications. 2019 ; Vol. 10, No. 1.
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