Targeting CANDI. promotes caspase-8/RIP1-dependent apoptosis in liver cancer cells

Cullin-associated NEDD8-dissociated 1 (CANDI) plays a vital role in regulating the activity of Cullin-RING ubiquitin ligases (CRLs), which are frequently dysregulated in cancer. However, the role of CANDI in hepatocellular carcinoma (HCC) remains unknown. Here, we found that CANDI was overexpressed in HCC tissues compared to corresponding adjacent liver tissues (71.7% vs I6.7%); high expression of CANDI was associated with poor overall survival (40.7 vs 57.3 months, P=0.0013); and CANDI was an independent risk factor for the prognosis of HCC patients (N=138, P=0.018). Functional studies revealed that CANDI knockdown efficiently suppressed the proliferation of liver cancer cells by activating caspase-8-dependent mitochondrial apoptosis. We also observed a mutual activation loop between caspase-8 and Receptor Interacting Protein 1 (RIPI), which amplified CANDI knockdown -induced apoptotic signals in the cells. Furthermore. RIPI inhibitor Necrostatin-1 eliminated the activation of caspase-8. In conclusion, our study pioneered in reporting high CAND1 expression as a predictor of poor prognosis for HCC patients. CANDI silencing suppressed HCC cell proliferation by inducing caspase-8/RIP1-dependent apoptosis. These findings supported that CANDI_ could be a new therapeutic target for liver cancer.