APCCDC20-mediated degradation of PHD3 stabilizes HIF-1a and promotes tumorigenesis in hepatocellular carcinoma
Min Shi, Weiqi Dai, Rongrong Jia, Qinghui Zhang, Jue Wei, Yugang Wang, Shihao Xiang, Bin Liu, Ling Xu
Abstract
CDC20 regulates cell cycle progression by targeting key substrates for destruction, but its role in hepatocellular carcinoma (HCC) tumorigenesis remains to be explored. Here, by using weighted gene co-expression network analysis (WGCNA), we identified CDC20 as a hub gene in HCC. We demonstrated that CDC20 expression is correlated with HIF-1 activity and overall survival (OS) of clinic HCC patients. The activity of HIF-1 is regulated by the stability of HIF-1a subunit, which is hydroxylated by oxygen-dependent prolyl hydroxylase enzymes , the PHDs. In addition, we show that genetic ablation or pharmacological inhibition of CDC20 can accelerate the degradation of HIF-1a and impair VEGF secretion in HCC cells. Mechanistically, we found that CDC20 binds to the destruction-box (D-box) motif present in the PHD3 protein to promote its polyubiquitination and degradation. The depletion of endogenous PHD3 in CDC20 knockdown HCC cells greatly attenuated the decline of HIF-1a protein and restored the secretion of VEGF. In contrast, overexpression of a non-degradable PHD3 mutant significantly inhibited the proliferation of HCC cells both in vitro and in vivo. Collectively, our findings indicate that CDC20 plays a crucial role in the development of HCC by governing PHD3 protein. • WGCNA analysis shows that CDC20 is closely related to HCC. • Depletion of CDC20 in HCC cells leads to tumor growth retardation and HIF-1a signaling pathway inactivation. • CDC20 stabilizes HIF-1a protein under normoxic condition. • CDC20 interacts with and targets PHD3 for proteasomal degradation in a D-box-Dependent Manner. • Failure to degrade PHD3 inhibits HCC development.