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

## TL;DR

CUL4B promotes liver cancer growth and drug resistance by degrading a protein called FUS, which affects tumor-suppressing miRNA and activates cancer pathways.

## Contribution

This study identifies CUL4B as a novel driver of HCC progression and oxaliplatin resistance through FUS degradation and miR-143-3p suppression.

## Key findings

- CUL4B is upregulated in HCC tissues and correlates with poor patient prognosis.
- CUL4B knockdown increases miR-143-3p levels and enhances oxaliplatin sensitivity in HCC cells.
- CUL4B promotes FUS ubiquitination and degradation, impairing miR-143-3p formation and activating KRAS signaling.

## Abstract

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 CRL4BDTL 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.