TRIM29 promotes liver metastasis via enhancing hepatic colonization by stabilizing FAM83H to regulate keratin network...

Liver metastasis is a frequent and severe event of colorectal cancer (CRC), and patients with liver metastases typically exhibit poor prognosis, high recurrence rates and low responsiveness to treatment. However, the precise molecular mechanisms underlying the liver metastasis in CRC remain poorly understood. In this study, through a comprehensive multi-omics approach, we here identify CRC cells with high tripartite motif-containing protein 29 (TRIM29) expression as the critical subset responsible for liver metastasis. Omics-sequencing pathway analyses combined with in vitro functional assays revealed that CRC cells expressing high TRIM29 expression displayed enhanced cell adhesion, proliferation and liver metastasis capabilities. Mechanistically, TRIM29 interacts with FAM83H and stabilizes it by reducing its ubiquitination and degradation, thereby redistributing cellular keratins, which activates the NF-κB pathway and upregulates PLXNB2 expression to enhance cell adhesion and proliferation to promote hepatic colonization and drive CRC liver metastasis. Interestingly, TRIM29 upregulates the expression of PLXNB2 that can bind to the hepatocyte-specific ligand SEMA4G. Importantly, targeting TRIM29-FAM83H-elicited keratin redistribution and PLXNB2 elevation effectively abrogated CRC liver metastasis. Our findings position TRIM29 as a central driver of liver metastasis in CRC and highlight its potential as a therapeutic target for reducing the risk of liver metastasis in patients.