Format

Send to

Choose Destination
Nat Commun. 2019 May 13;10(1):2130. doi: 10.1038/s41467-019-10044-z.

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

Author information

1
Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
2
MRI and µCT Service Group, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
3
Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, MD, USA.
4
Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, 69126, Germany.
5
Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, 69120, Germany.
6
Department I of Internal Medicine and Center for Integrated Oncology, University of Cologne, Cologne, 50937, Germany.
7
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691, Stockholm, Sweden.
8
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), ECCPS, Member of the DZL, Justus-Liebig University, Giessen, 35392, Germany.
9
Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany. soni.pullamsetti@mpi-bn.mpg.de.
10
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), ECCPS, Member of the DZL, Justus-Liebig University, Giessen, 35392, Germany. soni.pullamsetti@mpi-bn.mpg.de.

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.

PMID:
31086178
PMCID:
PMC6513860
DOI:
10.1038/s41467-019-10044-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center