Collagen Prolyl Hydroxylases Regulate HIF-α Levels Independently of pVHL in ccRCC

The hypoxia-inducible factors, HIF-1 and HIF-2, are master regulators of the hypoxia response. Under ambient conditions, both are hydroxylated by the HIF prolyl hydroxylases (HIF PHDs) resulting in ubiquitination by the pVHL E3 ligase complex, leading to subsequent proteasomal degradation. During hypoxia, the HIF PHDs are inhibited, resulting in HIF- stabilization and transcriptional activation of genes involved in the adaptation to hypoxia. Previous studies have shown that the collagen PHD, P4HA1, which promotes proline hydroxylation of collagen, inhibits the HIF PHDs by modulating levels of -ketoglutarate and succinate, thus enhancing HIF-1 stability by preventing pVHL-mediate degradation. Here, we investigate the role of collagen PHDs in the regulation of HIF-1/2 in the setting of pVHL deficiency in ccRCC. We show that the collagen PHDs P4HA1 and P4HA2 are required for HIF-1 translation and HIF-2 transcription and translation independently of pVHL function, through a mechanism regulated in part by P4HA1/2-driven collagen production. Thus, we reveal a novel pVHL-independent mechanism of HIF-1/2 regulation driven by P4HA1/2 in ccRCC. Since the HIFs have been strongly implicated in ccRCC initiation and progression, our data suggests that inhibition of P4HA1/2 may be a promising therapeutic strategy in ccRCC.