Hypoxia Signaling

Hypoxia (low O2) is a pathophysiological condition resulting from the imbalance between cellular O2 consumption and vascular perfusion. Hypoxia is a common feature of solid tumors associated with increased chemoradioresistance and poor patient prognosis. Metazoans have evolved mechanisms of adaptation to hypoxia that are mediated by hypoxia inducible factors (HIFs), a family of heterodimeric basic-helix-loop-helix transcription factors composed of an O2-regulated HIF-α subunit (HIF-1α, HIF-2α and HIF-3α) and a constitutively-expressed HIF-1β subunit. In well-oxygenated cells, HIF-α subunits are hydroxylated on proline residues by the oxygen-dependent prolyl-4-hydroxylases (PHDs). Proline hydroxylation allows the binding to the von Hippel–Lindau protein (pVHL), an E3 ubiquitin-ligase targeting HIF-α for proteasomal degradation. In addition, HIF-α undergoes asparaginyl hydroxylation by factor inhibiting HIF-1 (FIH) under non-hypoxic conditions, which prevents binding of HIF-α to the co-activators p300/CBP. Under hypoxia, PHD and FIH activity is substrate limited, resulting in rapid HIF-α accumulation, nuclear translocation and dimerization with HIF-1β. Transactivation occurs upon HIF-1 binding to DNA consensus sequences within the promoter of target genes, defined as hypoxia responsive elements (HREs). HIF-1 promotes the expression of hundreds of genes involved in cell autonomous and non-autonomous adaptations to hypoxia. Examples of genes and their functions are found in the diagram. HIF-α can be upregulated at the protein level via mTOR or at the mRNA level via STAT3 and NF-κB signaling. HIF-1 exerts pleiotropic effects on both cancer and stromal cells. For example, HIF-α-dependent expression of VEGF-A and PDGF-B induces angiogenesis by promoting proliferation and migration of pericytes, endothelial and vascular smooth muscle cells. In cancer-associated fibroblasts (CAFs), HIF-α mediates extracellular matrix (ECM) remodeling and metabolic reprogramming supporting cell survival. In addition, HIF-α promotes the expression of cytokines that suppress the adaptive immune system by stimulating the recruitment and activation of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and tumor associated macrophages (TAMs) leading to an immunosuppressive environment.

Selected Reviews:

• L. Schito and G.L. Semenza. (2016) Trends in Cancer, 2(12), 758-770.
• Gilkes, D.M., Semenza, G.L., and Wirtz, D. (2014) Nat Rev Cancer 14, 430−439.
• Karar, J. and Maity, A. (2011) Front Mol Neuro. 4, 51.
• LaGory, E.L. and Giaccia, A.J. (2016) Nat Cell Biol. 18, 356−365.
• Lee, K.E. and Simon, M.C. (2015) Cell 163, 1288.
• Masoud, G.N. and Li, W. (2015) Acta Pharmaceutica Sinica B. 5, 378−389.
• Palazon, A., Aragones, J., Morales-Kastresana, A. et al. (2012) Clin Cancer Res. 18, 1207−1213.

We would like to thank Dr. Luana Schito, Princess Margaret Cancer Centre and The Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada, for reviewing this diagram.

created February 2017