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

Ziyou Wu; Jian Zhang; Ziyao Jia; Ziyi Yang; Shilei Liu; Huakai Wang; Cheng Zhao; Jingwei Zhao; Qiuyi Tang; Yichen Xiong; Yue Yang; Yu Zhang; Zhe Zhou; Juanqing Yue; Fan Xiao; Quan Sun; Albie Gong; Wenyan Yao; Huaifeng Li; Xiaoling Song; Yuanyuan Ye; Yidi Zhu; Ping Dong; Fei Ma; Xiangsong Wu; Wei Gong

doi:10.1016/j.canlet.2024.216923

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

Cancer Lett. 2024 May 1:592:216923. doi: 10.1016/j.canlet.2024.216923. Online ahead of print.

Authors

Ziyou Wu¹, Jian Zhang¹, Ziyao Jia², Ziyi Yang³, Shilei Liu³, Huakai Wang³, Cheng Zhao³, Jingwei Zhao³, Qiuyi Tang³, Yichen Xiong³, Yue Yang³, Yu Zhang³, Zhe Zhou³, Juanqing Yue⁴, Fan Xiao⁵, Quan Sun⁶, Albie Gong⁷, Wenyan Yao⁸, Huaifeng Li³, Xiaoling Song³, Yuanyuan Ye³, Yidi Zhu³, Ping Dong³, Fei Ma⁹, Xiangsong Wu¹⁰, Wei Gong¹¹

Affiliations

¹ Department 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.
² Shanghai 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.
³ Department 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.
⁴ Department of Pathology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶ Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁷ Biochemistry, Faculty of Science, The University of British Columbia, Vancouver, Canada.
⁸ Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁹ Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: mafei@xinhuamed.com.cn.
¹⁰ Department 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. Electronic address: wuxiangsong@xinhuamed.com.cn.
¹¹ Department 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. Electronic address: gongwei@xinhuamed.com.cn.

PMID: 38697462
DOI: 10.1016/j.canlet.2024.216923

Abstract

Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.

Keywords: Gallbladder cancer; Liver metastasis; Mitophagy; TAT; TRIM21.