1. APC
- Author
-
Min, Shi, Wei-Qi, Dai, Rong-Rong, Jia, Qing-Hui, Zhang, Jue, Wei, Yu-Gang, Wang, Shi-Hao, Xiang, Bin, Liu, and Ling, Xu
- Subjects
Male ,Mice, Inbred BALB C ,Carcinoma, Hepatocellular ,Cdc20 Proteins ,Protein Stability ,Liver Neoplasms ,Ubiquitination ,Mice, Nude ,Apoptosis ,Hypoxia-Inducible Factor 1, alpha Subunit ,Prognosis ,Xenograft Model Antitumor Assays ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Mice ,Proteolysis ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Cell Proliferation - 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.
- Published
- 2020