Journal Article

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

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

2019

Overview

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. Pulmonary hypertension is characterized by a metabolic switch similar to the Warburg effect in cancer. Here Dabral et al. describe a RASSF1a-HIF-1α feedforward loop driving the Warburg effect both in a mouse model of hypoxia-induced pulmonary hypertension and a subset of human cancer cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/109 / 13/51 / 13/89 / 14 / 38 / 38/15 / 42 / 692/699/1785 / 692/699/75/243 / 96 / Animals / Binding sites / Cancer / Cell Hypoxia / Disease Models, Animal / Glycolysis / HEK293 Cells / HeLa Cells / Humanities and Social Sciences / Humans / Hydroxylation / Hypertension / Hypertension, Pulmonary - pathology / Hypertension, Pulmonary - surgery / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Kinases / Lung - blood supply / Lung - pathology / Lung - surgery / Lung cancer / Lung diseases / Lung Neoplasms - pathology / Male / Mice / Mice, Knockout / multidisciplinary / Myocytes, Smooth Muscle / NADPH Oxidase 1 - metabolism / Phosphorylation / Primary Cell Culture / Promoter Regions, Genetic - genetics / Proteasomes / Protein Binding / Protein kinase C / Protein Kinase C - metabolism / Proteins / Proteolysis / Pulmonary Artery - cytology / Pulmonary hypertension / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Transcription / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumors / Vascular diseases