TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited thera-peutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the inva-sion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Automated summary

This study identified TRIM21 as a protein that inhibits invasion and metastasis in colorectal cancer through its interaction with MST2. It was also found that the antidepressant vilazodone can exert anti-metastatic effects by binding to TRIM21. These findings reveal a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling pathway, and suggest that vilazodone could be repurposed as an anti-tumor drug to inhibit colorectal cancer metastasis by targeting TRIM21.