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

Ziyou Wu ¹, Jian Zhang ¹, Ziyao Jia ²

¹Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, China; Biliary Disease Research Institute of Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China; Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China.
⁴Department of Pathology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁷Biochemistry, Faculty of Science, The University of British Columbia, Vancouver, Canada.
⁸Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁹Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

⁰Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, China; Biliary Disease Research Institute of Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cancer Letters +

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May 2, 2024

View abstract on PubMed

Summary

Tyrosine aminotransferase (TAT) drives liver metastasis in gallbladder cancer (GBC) by promoting mitophagy. Targeting TAT and its interaction with TRIM21 offers a potential therapeutic strategy for GBC patients.

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.

Keywords:

Gallbladder cancer Liver metastasis Mitophagy TAT TRIM21