Journal article

Publication year: 2019

Journal: Nature Communications

Volume number: 10

eISSN: 2041-1723

Open access status: Gold

DOI Link: https://doi.org/10.1038/s41467-019-10044-z

Publisher: Nature Research

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 alpha (HIF-1 alpha) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1 alpha, 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-1 alpha forms a feedforward loop driving hypoxia signaling in PH and cancer.

Harvard Citation style: Dabral, S., Muecke, C., Valasarajan, C., Schmoranzer, M., Wietelmann, A., Semenza, G., et al. (2019) A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension, Nature Communications, 10, Article 2130. https://doi.org/10.1038/s41467-019-10044-z

APA Citation style: Dabral, S., Muecke, C., Valasarajan, C., Schmoranzer, M., Wietelmann, A., Semenza, G., Meister, M., Muley, T., Seeger-Nukpezah, T., Samakovlis, C., Weissmann, N., Grimminger, F., Seeger, W., Savai, R., & Pullamsetti, S. (2019). A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nature Communications. 10, Article 2130. https://doi.org/10.1038/s41467-019-10044-z