Integrated Multiomics Reveals Silencing of has_circ_0006646 Promotes TRIM21‐Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis

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. Has_circ_0006646 (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. Has_circ_0006646, a metastasis‐associated circRNA that is upregulated in HCC cells and tissues, can prevent interaction between NCL and the E3 ligase TRIM21 to reduce the ubiquitination degradation of NCL. This study expands the understanding of the epigenetic regulatory background of HCC metastasis and provides an exploitable therapeutic strategy for clinical treatment.