Cezanne (OTUD7B) regulates HIF-1a homeostasis in a proteasome-independent manner

The transcription factor HIF-1a is essential for cells to rapidly adapt to low oxygen levels (hypoxia). HIF-1a is frequently deregulated in cancer and correlates with poor patient prognosis. Here, we demonstrate that the deubiquitinase Cezanne regulates HIF-1a homeostasis. Loss of Cezanne decreases HIF-1a target gene expression due to a reduction in HIF-1a protein levels. Surprisingly, although the Cezanne-regulated degradation of HIF-1a depends on the tumour suppressor pVHL, hydroxylase and proteasome activity are dispensable. Our data suggest that Cezanne is essential for HIF-1a protein stability and that loss of Cezanne stimulates HIF-1a degradation via proteasome-independent routes, possibly through chaperone-mediated autophagy.