Hypoxia, defined as a reduction in the amount of oxygen available to a cell, tissue, or organism, is a fundamental and life-threatening biological phenomenon. Hypoxia signaling mediated via hypoxia inducible factor-1 (HIF-1α) plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by hyperproliferative vascular cells and a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumor suppressor. Although majorly studied in the field of malignancies, studies on its potential role in primary cells under different physiological cues such as hypoxia are unexplored.Here, we identify a molecular mechanism, where RASSF1A acts a crucial regulator of HIF-1α signaling. Upon hypoxia, RASSF1A protein is initially stabilized by NOX-1- and protein kinase C- dependent phosphorylation, and is subsequently transcriptionally upregulated by HIF-1α. Vice-versa, RASSF1A directly interacts with HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, leading to its nuclear entry and transactivation of HIF-1 target genes (pyruvate dehydrogenase kinase 1 [PDK1], hexokinase 2 [HK2], and lactate dehydrogenase [LDHA]). This hitherto unknown feed-forward loop between RASSF1A and HIF-1α promotes the glycolytic shift. 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. The underlying molecular mechanisms unveiled here (Fig. 1) provide future targets for therapeutic intervention, to be exploited for improved therapy of these diseases.
Nat Commun. 2019 May 13;10(1):2130. doi: 10.1038/s41467-019-10044-z