Journal Article

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

Liu, Yanfeng, Li, Hongchang, Yang, Xiaolu, Chen, Liang, Tao, Shishi, Li, Zhihuan, Wan, Xiaochun, Liao, Lijuan, Li, Yang, Lin, Lilong

2020

نظرة عامة

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. The unfolded protein response allows tumour cells to adapt to ER stress, and aberrant activation of Nrf2 confers cancer progression. Here, the authors show that TRIM25 is induced during ER stress and promotes tumour cell survival by targeting Keap1 for degradation, leading to Nrf2 activation.

• الناشر: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• موضوع: 13 / 13/31 / 13/51 / 45/88 / 631/337 / 631/67/1504/1610/4029 / 692/4028/67/1504/1610 / 82/58 / Activation / Animals / Antioxidants / Cancer / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Cell Line, Tumor / Cell survival / Cell Survival - physiology / Degradation / Depletion / Endoplasmic reticulum / Endoplasmic Reticulum Stress - physiology / Endoribonucleases - metabolism / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Hepatocellular carcinoma / Homeostasis / Humanities and Social Sciences / Humans / Kelch-Like ECH-Associated Protein 1 - metabolism / Liver / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Male / Mice / Mice, Inbred BALB C / Mice, Nude / multidisciplinary / NF-E2-Related Factor 2 - metabolism / Oxidants / Oxidative Stress / Oxidizing agents / Protein folding / Protein-Serine-Threonine Kinases - metabolism / Proteins / Science / Science (multidisciplinary) / Signal Transduction / Survival / Transcription Factors - genetics / Transcription Factors - metabolism / Tripartite Motif Proteins - genetics / Tripartite Motif Proteins - metabolism / Tumor cells / Tumors / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation