Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.

Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.