Hypoxia inducible factors (HIFs) are the key transcription factors that allow cancer cells to survive hypoxia. HIF's stability is mainly controlled by von Hippel–Lindau (pVHL)‐mediated ubiquitylation. Unlike sporadic clear‐cell renal carcinomas, VHL mutation is rarely observed in hepatocellular carcinoma (HCC) and the regulatory mechanisms of pVHL‐HIF signaling remain elusive. Here, it is shown that deubiquitylase ovarian tumor domain‐containing 6B (OTUD6B) suppresses HCC metastasis through inhibiting the HIF activity. OTUD6B directly interacts with pVHL, decreases its ubiquitylation and proteasomal degradation to reduce HIF‐1α accumulation in HCC cells under hypoxia. Surprisingly, OTUD6B limits the ubiquitylation of pVHL independent of its deubiquitylase activity. OTUD6B couples pVHL and elongin B/C to form more CBCVHL ligase complex, which protects pVHL from proteasomal degradation. Depletion of OTUD6B results in the dissociation of CBCVHL complex and the degradation of pVHL by Trp Asp repeat and suppressors of cytokine signaling box‐containing protein 1 (WSB1). In human HCC tissues, the protein level of OTUD6B is positively correlated with pVHL, but negatively with HIF‐1α and vascular endothelial growth factor. Low expression of OTUD6B predicts poor patient survival. Furthermore, OTUD6B gene is a direct transcriptional target of HIF‐1α and upregulated upon hypoxia. These results indicate a previously unrecognized feedback loop consisting of OTUD6B, pVHL, and HIF‐1α, and provide insights into the targeted hypoxic microenvironment for HCC therapy.
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