Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis

Hongkun Cai; Jingyuan Zhao; Qiyue Zhang; Heyu Wu; Yan Sun; Feng Guo; Yingke Zhou; Gengdu Qin; Wentao Xia; Yuhan Zhao; Xueyi Liang; Shilin Yin; Yang Qin; Dan Li; Heshui Wu; Dianyun Ren

doi:10.1016/j.bbadis.2024.167183

Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 22;1870(5):167183. doi: 10.1016/j.bbadis.2024.167183. Online ahead of print.

Authors

Hongkun Cai¹, Jingyuan Zhao¹, Qiyue Zhang¹, Heyu Wu², Yan Sun¹, Feng Guo¹, Yingke Zhou¹, Gengdu Qin¹, Wentao Xia¹, Yuhan Zhao¹, Xueyi Liang¹, Shilin Yin¹, Yang Qin¹, Dan Li³, Heshui Wu⁴, Dianyun Ren⁵

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 Department of Operating Room, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
³ Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: lidanld@hust.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.
⁵ 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: rendianyun@hust.edu.cn.

PMID: 38657551
DOI: 10.1016/j.bbadis.2024.167183

Abstract

Background: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive.

Methods: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo.

Results: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15.

Conclusions: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

Keywords: IGF2BP2; Methylation; N(6)-methyladenosine; Pancreatic cancer; Phase separation; TLR4; TRIM15; Ubiquitination.