| First Author | Dabral S | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 2130 |
| PubMed ID | 31086178 | Mgi Jnum | J:275531 |
| Mgi Id | MGI:6305555 | Doi | 10.1038/s41467-019-10044-z |
| Citation | Dabral S, et al. (2019) A RASSF1A-HIF1alpha loop drives Warburg effect in cancer and pulmonary hypertension. Nat Commun 10(1):2130 |
| abstractText | 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-1alpha) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1alpha, 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-1alpha forms a feedforward loop driving hypoxia signaling in PH and cancer. |
