2. Academic Validation
  3. TRIM15 promotes the invasion and metastasis of pancreatic cancer cells by mediating APOA1 ubiquitination and degradation

TRIM15 promotes the invasion and metastasis of pancreatic cancer cells by mediating APOA1 ubiquitination and degradation

  • Biochim Biophys Acta Mol Basis Dis. 2021 Nov 1;1867(11):166213. doi: 10.1016/j.bbadis.2021.166213.
Yan Sun 1,  Dianyun Ren 1,  Chong Yang 2,  Wenhao Yang 2,  Jingyuan Zhao 1,  Yingke Zhou 1,  Xin Jin 3,  Heshui Wu 4
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, Sichuan, China.
  • 3 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. Electronic address: jinxinxy2@csu.edu.cn.
  • 4 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: heshuiwu@hust.edu.cn.
PMID: 34311082 DOI: 10.1016/j.bbadis.2021.166213
Abstract

Most pancreatic ductal adenocarcinomas (PDACs) are diagnosed at an advanced or metastatic stage. Metastasis is the one of the major obstacles to prolonging the survival time of patients with pancreatic Cancer. The tripartite motif (TRIM) family member TRIM15 has been implicated in Cancer development. Our bioinformatics analysis indicated that TRIM15 might be involved in the regulation of pancreatic Cancer metastasis. However, the role of TRIM15 in PDAC remains unclear. Metabolic reprogramming involving dysregulated lipid synthesis is common in patients with PDAC. Targeting lipid anabolism has been proposed as a strategy to treat PDAC. In this study, we demonstrated that TRIM15 expression was elevated in PDAC tissues, and this elevated expression was associated with a poor prognosis. TRIM15 silencing suppressed the invasion and migration of pancreatic Cancer cells. Importantly, the mass spectrometry analysis suggested that Apolipoprotein A1 (APOA1), the main component of high-density lipoprotein (HDL) that is involved in lipid transport and metabolism, might be one of the binding partners of TRIM15. Further experiment indicated that TRIM15 interacted with APOA1 through its PRY/SPRY domain and promoted APOA1 polyubiquitination via its RING domain. APOA1 degradation enhanced lipid anabolism and promoted lipid droplet accumulation in pancreatic Cancer cells. Furthermore, we showed that TRIM15 might promote PDAC metastasis by regulating lipid metabolism via the APOA1-LDLR axis. Consequently, targeting the TRIM15-APOA1-LDLR axis may be a strategy to inhibit PDAC metastasis by blocking triglyceride synthesis.

Keywords

Apolipoprotein A1; Invasion; Lipid metabolism; Low-density lipoprotein receptor; Metastasis; PDAC; Triglyceride; Tripartite motif 15; Ubiquitination.

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