Tripartite motif 59 (TRIM59) is a member of Tripartite motif protein family, which is frequently increased in many human cancers. However, the molecular mechanism of TRIM59 in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we report that TRIM59 plays an essential role in growth of HCC. We analyzed RNA sequencing data to explore abnormally expressed TRIM59 in HCC. The effects of TRIM59 on HCC were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, xenograft model, immunohistochemistry, immunofluorescence and western blot). The mechanism of TRIM59 action was explored through co-immunoprecipitation, immunofluorescence, mass spectrometry and bioinformatics. TRIM59 expression is up-regulated in HCC tissues. A high level of TRIM59 expression is correlated with poor overall and disease-free survival of HCC patients. Knockdown of TRIM59 attenuated proliferation, induced cells arrested at G1/S phase and reduced tumor growth in the mouse xenograft model. Ectopic expression of TRIM59 had the opposite results. Mechanistically, TRIM59 promoted growth and regulated cell cycle. Further studies indicated that TRIM59 might interacted physically with PPM1B, which has been reported to negatively regulate CDKs phosphorylation. We also discovered that TRIM59 increased degradation of PPM1B. TRIM59 overexpression in HCC patients correlated with reduced expression of PPM1B and increased CDKs phosphorylation and cell cycle proteins. Our findings demonstrate that TRIM59 promotes growth by PPM1B/CDKs signaling pathway, indicating a new prognostic biomarker candidate and a potential antitumor target for HCC.

中文翻译：

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TRIM59促进肝细胞癌中的肿瘤生长，并通过降解蛋白磷酸酶1B来调节细胞周期。

Tripartite母题59（TRIM59）是Tripartite母题蛋白家族的一员，在许多人类癌症中该家族经常增加。但是，尚未完全阐明TRIM59在肝细胞癌（HCC）中的分子机制。在这项研究中，我们报道了TRIM59在肝癌的生长中起着至关重要的作用。我们分析了RNA测序数据，以探索肝癌中异常表达的TRIM59。通过体外和体内测定（即CCK-8测定，菌落形成测定，流式细胞术测定，异种移植模型，免疫组织化学，免疫荧光和蛋白质印迹）研究了TRIM59对HCC的作用。通过共同免疫沉淀，免疫荧光，质谱和生物信息学探索了TRIM59作用的机制。TRIM59表达在肝癌组织中上调。高水平的TRIM59表达与肝癌患者总体生存状况差和无病生存相关。在小鼠异种移植模型中，敲低TRIM59可减缓增殖，诱导细胞停留在G1 / S期，并减少肿瘤的生长。TRIM59的异位表达结果相反。从机理上讲，TRIM59促进生长并调节细胞周期。进一步的研究表明，TRIM59可能与PPM1B发生物理相互作用，据报道PPM1B负调节CDKs磷酸化。我们还发现，TRIM59增加了PPM1B的降解。在肝癌患者中，TRIM59过表达与PPM1B表达降低，CDKs磷酸化和细胞周期蛋白增加有关。我们的发现表明TRIM59通过PPM1B / CDKs信号通路促进生长，