TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway
TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway
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TRIM25通过靶向Keap1-Nrf2通路促进肝细胞癌细胞存活和生长
DOI：
10.1038/s41467-019-14190-2
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发表时间：
2020-01-17
影响因子：
16.6
通讯作者：
Chen, Liang
中科院分区：
文献类型：
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作者：
Liu, Yanfeng;Tao, Shishi;Chen, Liang
肿瘤细胞通常表现出增强的能力，以维持内质网（ER）的稳态在不利的条件下，但其潜在的机制还没有得到很好的定义。在这里，通过对所有人TRIM蛋白的评估，我们发现TRIM25在ER应激时被显著诱导。TRIM25的上调改善氧化应激，促进ER相关降解（ERAD），并减少UPR途径中的IRE1信号传导。相反，TRIM 25的耗尽导致ER应激并在体外和体内减弱肿瘤细胞生长。从机制上讲，TRIM25通过泛素化和降解直接靶向Keap1。这导致Nrf2激活，从而增强抗氧化防御和细胞存活。在肝细胞癌（HCC）异种移植物和标本中，TRIM25表达与Nrf2表达呈正相关，与Keap1表达呈负相关。此外，高TRIM25表达与HCC患者的生存率差相关。这些发现表明TRIM 25是ER稳态的调节剂和肿瘤治疗的潜在靶点。
Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.