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

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.