TY - JOUR
T1 - A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension
AU - Dabral, Swati
AU - Muecke, Christian
AU - Valasarajan, Chanil
AU - Schmoranzer, Mario
AU - Wietelmann, Astrid
AU - Semenza, Gregg L.
AU - Meister, Michael
AU - Muley, Thomas
AU - Seeger-Nukpezah, Tamina
AU - Samakovlis, Christos
AU - Weissmann, Norbert
AU - Grimminger, Friedrich
AU - Seeger, Werner
AU - Savai, Rajkumar
AU - Pullamsetti, Soni S.
N1 - Funding Information:
The authors would like to thank Prof. Reinhard Dammann, Institute for Genetics, Justus-Liebig University Giessen for excellent suggestions with regard to RASSF1A and providing all the RASSF1A and RASSF1C constructs; Prof. Joachim Fandrey, Institute of Physiology, University of Duisburg-Essen for support with cell lines for RASSF1screening. The authors thank Uta Eule, Vanessa Golchert, Ewa Bieniek, and Natascha Wilker for the valuable technical assistance. The Max Planck Society, the Scientific and Economic Excellence in Hesse (LOEWE) Program, DFG, SFB 1213 (Project A01, A05, A06, A07), and the Excellence Cluster 147 Cardio-Pulmonary System (ECCPS, EXC 147) supported this work.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-10044-z
DO - 10.1038/s41467-019-10044-z
M3 - Article
C2 - 31086178
AN - SCOPUS:85065699276
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2130
ER -