TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway

Yanfeng Liu, Shishi Tao, Lijuan Liao, Yang Li, Hongchang Li, Zhihuan Li, Lilong Lin, Xiaochun Wan, Xiaolu Yang () and Liang Chen ()
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Yanfeng Liu: Chinese Academy of Sciences
Shishi Tao: Chinese Academy of Sciences
Lijuan Liao: Chinese Academy of Sciences
Yang Li: Chinese Academy of Sciences
Hongchang Li: Chinese Academy of Sciences
Zhihuan Li: Dongguan Enlife Stem Cell Biotechnology Institute
Lilong Lin: Dongguan Enlife Stem Cell Biotechnology Institute
Xiaochun Wan: Chinese Academy of Sciences
Xiaolu Yang: University of Pennsylvania
Liang Chen: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-14190-2

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