TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Liver metastasis is a frequent and poor prognostic indicator in gallbladder cancer (GBC).
• The molecular mechanisms driving GBC liver metastasis are not well understood.

Purpose of the Study:

• To investigate the role of tyrosine aminotransferase (TAT) in gallbladder cancer liver metastasis.
• To elucidate the molecular mechanisms by which TAT contributes to GBC progression.

Main Methods:

• Analysis of TAT expression in GBC tissues and correlation with clinical outcomes.
• In vitro and in vivo experiments assessing the effects of TAT overexpression and knockdown on GBC cell behavior and metastasis.
• Investigation of TAT's interaction with cardiolipin and mitophagy.
• Identification and characterization of TRIM21's role in regulating TAT ubiquitination and function.

Main Results:

• Tyrosine aminotransferase (TAT) is frequently upregulated in GBC and associated with liver metastasis and poor prognosis.
• TAT overexpression enhances GBC cell migration, invasion, and liver metastasis, while TAT knockdown inhibits these processes.
• TAT promotes liver metastasis by directly binding cardiolipin, leading to cardiolipin-dependent mitophagy.
• Tripartite Motif Containing 21 (TRIM21) interacts with TAT, mediating K63-linked ubiquitination that impairs TAT dimerization and mitochondrial localization, thereby inhibiting GBC cell invasion and migration.

Conclusions:

• Tyrosine aminotransferase (TAT) is a novel driver of liver metastasis in gallbladder cancer.
• The TAT-cardiolipin-mitophagy axis and the TRIM21-mediated regulation of TAT represent potential therapeutic targets for inhibiting GBC liver metastasis.