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

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  • Yanfeng Liu

    (Chinese Academy of Sciences
    Shanghai Jiao Tong University)

  • 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)

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.

Suggested Citation

  • Yanfeng Liu & Shishi Tao & Lijuan Liao & Yang Li & Hongchang Li & Zhihuan Li & Lilong Lin & Xiaochun Wan & Xiaolu Yang & Liang Chen, 2020. "TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14190-2
    DOI: 10.1038/s41467-019-14190-2
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    Cited by:

    1. Changzhou Cai & Huailu Ma & Jin Peng & Xiang Shen & Xinghua Zhen & Chaohui Yu & Pumin Zhang & Feng Ji & Jiewei Wang, 2023. "USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Hui Yang & Qingqing Li & Xingxing Chen & Mingzhe Weng & Yakai Huang & Qiwen Chen & Xiaocen Liu & Haoyu Huang & Yanhuizhi Feng & Hanyu Zhou & Mengying Zhang & Weiya Pei & Xueqin Li & Qingsheng Fu & Lia, 2024. "Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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