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TRIM21 participates in cancer metabolism, glycolysis, immunity, chemosensitivity and metastasis by targeting various substrates for ubiquitination. TRIM21 serves as a prognosis marker for human hepatocellular carcinoma (HCC), but the mechanism by which TRIM21 regulates HCC tumorigenesis and progression remains elusive. In this study, we demonstrated that TRIM21 protein levels were elevated in human HCC. Elevated TRIM21 expression was associated with HCC progression and poor survival. Knockdown of TRIM21 in HCC cell lines significantly impaired cell growth and metastasis and enhanced sorafenib\u2010induced toxicity. Mechanistically, we found that knockdown of TRIM21 resulted in cytosolic translocation and inactivation of YAP. At the molecular level, we further identified that TRIM21 interacted and induced ubiquitination of MST1, which resulted in MST1 degradation and YAP activation. Knockdown of MST1 or overexpression of YAP reversed TRIM21 knockdown\u2010induced impairment of HCC growth and chemosensitivity. Taken together, the current study demonstrates a novel mechanism that regulates the Hippo pathway and reveals TRM21 as a critical factor that promotes growth and chemoresistance in human HCC.<\/jats:p>","DOI":"10.1111\/cas.16134","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T05:55:17Z","timestamp":1710309317000},"page":"1476-1491","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1\/<scp>YAP<\/scp> pathway"],"prefix":"10.1111","volume":"115","author":[{"given":"Bo","family":"Shu","sequence":"first","affiliation":[{"name":"Department of General Surgery, The Second Xiangya Hospital Central South University  Changsha Hunan 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