CUL4B promotes hepatocellular carcinoma progression and oxaliplatin resistance by facilitating FUS degradation

Cullin4B (CUL4B), which functions as a scaffold protein within the CUL4B-RING ubiquitin ligase complex (CRL4B), is frequently overexpressed in various cancers and exhibits oncogenic characteristics. However, its specific role in hepatocellular carcinoma (HCC) progression and drug resistance remains unclear. This study revealed that CUL4B is upregulated in HCC tissues, with elevated levels correlating with poor patient prognosis. A strong inverse relationship was observed between the expression of CUL4B and the tumor suppressor miR-143-3p in human HCC samples; CUL4B knockdown significantly increased miR-143-3p levels. Moreover, suppression of CUL4B inhibited HCC cell proliferation and enhanced sensitivity to oxaliplatin through miR-143-3p upregulation. Fused in sarcoma (FUS), an RNA-binding protein implicated in miRNA biogenesis, was identified as a novel CRL4B^DTL substrate. CUL4B facilitates FUS ubiquitination and subsequent degradation, thereby reducing FUS protein levels. This reduction impairs miR-143-3p formation, activates the KRAS signaling pathway, and promotes tumor progression and oxaliplatin resistance. In summary, this study provided compelling evidence that CUL4B knockdown may be a promising strategy for treating HCC and increasing tumor cell sensitivity to oxaliplatin therapy.