The VHL Tumor Suppressor Gene: Insights into Oxygen Sensing and Cancer

Abstract

Mammalian cells sense changes in oxygen and transduce that information into adaptive changes in gene expression using a conserved pathway that converges on the heterodimeric transcription factor called hypoxia-inducible factor (HIF), which contains a labile alpha subunit and a stable beta subunit. In the presence of oxygen, the alpha subunit is hydroxylated on one (or both) of two highly conserved prolyl residues by an Egg-Laying Defective Nine (EglN) [also called Prolyl Hydroxylase Domain (PHD)] dioxygenase, which recruits an ubiquitin ligase complex containing the VHL tumor suppressor gene product. Germline VHL mutations cause von Hippel-Lindau (VHL) disease, which manifest as angiogenic tumors such as hemangioblastomas and kidney cancers. Somatic VHL inactivation and deregulation of HIF (especially HIF2α) drives sporadic kidney cancers and an HIF2α inhibitor is showing promise for this disease. VHL, EglN1, and HIF2α polymorphisms have been linked to familial polycythemia and adaptation to high altitude. Orally available EglN inhibitors are being developed for the treatment of anemia and ischemic diseases.

Fig. 1

Pharmacological manipulation of the oxygen-sensing pathway. When oxygen is available an EglN (also called PHD) prolyl hydroxylase, such as EglN1 (also called PHD2), hydroxylates HIFα subunits on one of two prolyl residues, which then generates a binding site for an ubiquitin ligase containing the VHL gene product, pVHL. Once bound, pVHL earmarks the alpha subunit for proteasomal degradation. When oxygen levels are low, or pVHL is defective, HIFα becomes stable, dimerizes with HIFβ, and transcriptionally activates HIF-responsive genes such as EPO and VEGF. EPO is an example of a HIF-responsive gene that is exclusively regulated by HIF2 and HIF2 also appears to be the primary driver of pVHL-defective kidney cancers. Note that pVHL also has HIF-independent functions (not shown for simplicity) and that pVHL loss is not sufficient to cause kidney cancer (this requires additional cooperating genetic events). The small molecule PT-2385 (and related tool compound PT-2399) is being developed for the treatment of kidney cancer, while multiple EglN inhibitors, such as Roxadustat, Vadadustat, Molidustat, and Daprodustat, are undergoing clinical trials for anemia linked to chronic renal failure. Abbreviations: Eg1N, Egg-Laying Defective Nine; PHD, Prolyl Hydroxylase Domain; HIF, hypoxia-induced factor; VHL, von Hippel Lindau; EPO, erthropoeitin; VEGF, vascular endothelial growth factor.