1. TRIM65/NF2/YAP1 Signaling Coordinately Orchestrates Metabolic and Immune Advantages in Hepatocellular Carcinoma.
- Author
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Bian Z, Xu C, Wang X, Zhang B, Xiao Y, Liu L, Zhao S, Huang N, Yang F, Zhang Y, Xue S, Wang X, Pan Q, and Sun F
- Subjects
- Animals, Humans, Mice, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Cell Line, Tumor, Disease Models, Animal, Male, Mice, Inbred BALB C, Mice, Nude, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular genetics, Liver Neoplasms metabolism, Liver Neoplasms genetics, Signal Transduction genetics, Transcription Factors metabolism, Transcription Factors genetics, Tripartite Motif Proteins metabolism, Tripartite Motif Proteins genetics, Ubiquitin-Protein Ligases metabolism, Ubiquitin-Protein Ligases genetics, YAP-Signaling Proteins metabolism, YAP-Signaling Proteins genetics
- Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Significantly activated uridine nucleotide and fatty acid metabolism in HCC cells promote malignant proliferation and immune evasion. Herein, it is demonstrated that the tripartite motif 65 (TRIM65) E3 ubiquitin-protein ligase, O-GlcNAcylated via O-GlcNAcylation transferase, is highly expressed in HCC and facilitated metabolic remodeling to promote the accumulation of products related to uracil metabolism and palmitic acid, driving the progression of HCC. Mechanistically, it is showed that TRIM65 mediates ubiquitylation at the K44 residue of neurofibromatosis type 2 (NF2), the key protein upstream of classical Hippo signaling. Accelerated NF2 degradation inhibits yes-associated protein 1 phosphorylation, inducing aberrant activation of related metabolic enzyme transcription, and orchestrating metabolic and immune advantages. In conclusion, these results reveal a critical role for the TRIM family molecule TRIM65 in supporting HCC cell survival and highlight the therapeutic potential of targeting its E3 ligase activity to alter the regulation of proteasomal degradation., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
- Published
- 2024
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