RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma

Sorafenib, a first-line targeted drug for advanced hepatocellular carcinoma (HCC), has limited clinical application due to intrinsic/acquired resistance. In this study, we have identified the RNA-binding protein RBMS3 as a pivotal regulator involved in sorafenib resistance among patients with HCC. Loss- and gain-of-function experiments further demonstrate that downregulation of RBMS3 promotes angiogenesis and confers resistance to sorafenib by augmenting the capacity of HCC cells to express and secrete ANGPT2, while upregulation of RBMS3 reverse these phenotypes.Through immunoprecipitation mass spectrometry experiments and co-immunoprecipitation (co-IP), we further verified that RBMS3 can facilitate the K48-linked ubiquitination and subsequent protein degradation of ANGPT2 by recruiting the ubiquitin E3 ligase TRIM21 in an RNA-independent manner.Additionally, RBMS3 is found to be deleted in HCC tissues and exhibits a significant positive correlation with angiogenesis and resistance to sorafenib treatment. Importantly, the combination of ANGPT2 antibody in RBMS3-deficient HCC cells restores sensitivity to sorafenib both in vitro and in vivo. These findings uncovered a novel molecular basis for post-translational upregulation of ANGPT2, suggesting that RBMS3-loss plays an oncogenic role in HCC by promoting angiogenesis and conferring resistance to sorafenib treatment.