
Aberrant SUMOylation contributes to the progression of hepatocellular carcinoma (HCC), yet the molecular mechanisms have not been well elucidated. RING-type E3 ubiquitin ligase RNF146 is a crucial regulator of the Wnt/β-catenin signalling pathway, which is frequently hyperactivated in HCC. In this study, it is identified that SUMO3 can modify RNF146. By mutating all lysines in RNF146, this study found that K19, K61, K174 and K175 are the primary sites for SUMOylation. This study concludes that RNF146 SUMOylation at K19/K175 promotes its association with Axin and accelerates Axin degradation, enhancing β-catenin signalling and contributing to cancer progression. The findings reveal that RNF146 SUMOylation is a potential therapeutic target in HCC.
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