DUB-independent regulation of pVHL by OTUD6B suppresses hepatocellular carcinoma

Oxygen is vital for most living organisms.During the course of evolution, animals have developed a highly conserved and elegant pathway to regulate oxygen sensing that converges on the heterodimeric transcription factor called hypoxia-inducible factor (HIF), which contains HIF-1o, a labile alpha subunit and HIF-1β, a stable beta subunit (Wang et al., 1995;Kaelin & Ratcliffe, 2008).In the presence of oxygen, HIF-1α is hydroxylated on the proline-402 and proline-564 residues by the family of Egg-Laying Defective Nine dioxygenases (EglN),which are also called Prolyl Hydroxylase Domain (PHD) proteins (Bruick & McKnight, 2001;Epstein et al., 2001;Ivan et al., 2002).The proline hydroxylation post-translational modification subsequently recruits the Cullin 2VHL E3 ubiquitin ligase complex which comprises the von Hippel-Lindau tumor suppressor (pVHL), Elongin B, Elongin C, Rbx1 and Cullin 2 (Zhang et al., 2019).Specific recognition of the proline-hydroxylation modification by Cullin 2VHL leads to the ubiquitination and subsequent proteasomal degradation of HIF-1α.As such, under low oxygen conditions, deficit in the proline hydroxylation of HIF-1α would lead to its stabilization and activation, thus promoting the transcription of hundreds of target genes, such as vascular endothelial growth factor and erythropoietin (Zhang et al., 2019).These H IF-1α target genes normally serve to promote acute or chronic adaptation to hypoxia, facilitate angiogenesis and thus favor the growth of solid tumor (Wilson & Hay, 2011).