Integrated Multiomics Reveals Silencing of hascirc₀006646 Promotes TRIM21‐Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis

Abstract Recent studies suggest that circular RNA (circRNA) ‐mediated post‐translational modification of RNA‐binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi‐omics approach. Hascirc₀006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif‐containing 21 to reduce the proteasome‐mediated degradation of NCL via K48‐linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient‐derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi‐omics landscape of circRNA‐mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target.