Liver cancer is the sixth most common cancer and the third leading cause of cancer‐related death globally. Despite efforts being made in last two decades in cancer diagnosis and treatment, the 5‐year survival rate of liver cancer remains extremely low. 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‐induced 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‐induced 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.

中文翻译：

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TRIM21 通过改变 MST1/YAP 通路来调节肝细胞癌的生长和治疗反应

肝癌是全球第六大常见癌症，也是癌症相关死亡的第三大原因。尽管近二十年来在癌症诊断和治疗方面做出了努力，但肝癌的5年生存率仍然极低。TRIM21通过靶向多种底物进行泛素化，参与癌症代谢、糖酵解、免疫、化疗敏感性和转移。TRIM21 可作为人类肝细胞癌 (HCC) 的预后标志物，但 TRIM21 调节 HCC 肿瘤发生和进展的机制仍不清楚。在这项研究中，我们证明 TRIM21 蛋白水平在人类 HCC 中升高。TRIM21 表达升高与 HCC 进展和较差的生存率相关。HCC 细胞系中 TRIM21 的敲低显着损害细胞生长和转移，并增强索拉非尼诱导的毒性。从机制上讲，我们发现 TRIM21 的敲低导致 YAP 的胞质易位和失活。在分子水平上，我们进一步鉴定TRIM21相互作用并诱导MST1泛素化，从而导致MST1降解和YAP激活。MST1 的敲低或 YAP 的过表达可逆转 TRIM21 敲低引起的 HCC 生长和化疗敏感性损害。总而言之，当前的研究证明了一种调节 Hippo 通路的新机制，并揭示了 TRM21 作为促进人类 HCC 生长和化疗耐药的关键因素。