TRIM65/NF2/YAP1 Signaling Coordinately Orchestrates Metabolic and Immune Advantages in Hepatocellular Carcinoma.
Adv Sci (Weinh)
; 11(35): e2402578, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-39005234
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Transdução de Sinais
/
Carcinoma Hepatocelular
/
Ubiquitina-Proteína Ligases
/
Proteínas com Motivo Tripartido
/
Proteínas de Sinalização YAP
/
Neoplasias Hepáticas
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Adv Sci (Weinh)
Ano de publicação:
2024
Tipo de documento:
Article