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 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.
Highlights
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases
Ras association domain family 1A (RASSF1A) mRNA in different primary human cells, namely, human broncho-alveolar epithelial cells (HBECs), pulmonary arterial-smooth muscle cells (PASMCs), -adventitial fibroblasts (PAAFs) and –endothelial cells (PAECs) as compared to A549 cell line (Fig. 1a)
We identify RASSF1A as a hypoxia regulated protein that directly promotes hypoxia inducible factor-1 α (HIF-1α) protein stabilization and transcriptional activity in various human primary cells, thereby controlling the hypoxia-induced metabolic shift known as Warburg effect and cell proliferation
Summary
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Hypoxic signaling pathways are implicated in a plethora of physiological processes such as blood cell differentiation and organ morphogenesis[9,10] they are centrally involved in both malignant and non-malignant hyperproliferative disease processes This is since long known as Warburg effect driving a fundamental metabolic (glycolytic) switch in the cancer cells[11] and is operative in the prototype non-malignant hypoxia-driven disease, pulmonary hypertension characterized by vascular remodeling due to hyperproliferation of pulmonary vascular smooth muscle cells and adventitial fibroblasts[12]. Vice-versa, RASSF1A directly interacts with HIF-1α, leading to increased HIF-1α stabilization, 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 in hypoxiaexposed human primary cells. We provide genetic and clinical ex-vivo evidence for the function of this RASSF1A-HIF1α loop in human lung cancer and pulmonary hypertension
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