Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer

Abstract

Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel-Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.

Figure 1. Pharmacological control of HIF.

(A) In the presence of the cofactors oxygen and reduced iron, the EglN prolyl hydroxylases hydroxylate one (or both) of two prolyl residues in HIFα (for simplicity, only one hydroxylation event is depicted). Prolyl-hydroxylated HIFα is recognized by a ubiquitin ligase that uses pVHL as the substrate recognition module, leading HIFα to be polyubiquitylated and destroyed by the proteasome. HIF prolyl hydroxylase inhibitors (HIF PHIs) prevent the hydroxylation of HIF by inhibiting the EglNs by competing with 2-OG or iron. (B) HIFα binds to its partner protein ARNT. This complex can then recognize specific genomic DNA binding sites (hypoxia response elements [HREs]) and activate transcription. Belzutifan binds specifically to HIF2α and induces an allosteric change such that it can no longer bind to ARNT and hence to DNA. EloB, elongin B; EloC, elongin C; CUL2, cullin 2; RBX1, RING box protein 1.

Figure 2. HIF and genotype-phenotype correlations in VHL disease.

The degree to which different VHL alleles deregulate HIF, at least when tested in preclinical models, correlates with the risk of developing specific types of tumors in VHL disease. VHL alleles leading to the highest HIF levels, including true null VHL alleles, are associated with a high risk of hemangioblastoma and ccRCC, but not paraganglioma (type 1 VHL disease). VHL alleles associated with minimal HIF deregulation are associated with familial paraganglioma with few or no other stigmata of VHL disease (type 2C disease). Progressively higher HIF levels are associated with an increased risk of hemangioblastoma (type 2A disease) and, above a certain threshold, ccRCC (type 2B disease). It is possible that exceedingly high HIF levels actually suppress the development of paraganglioma in type 1 disease.