TRIM family proteins are defined as E3 ubiquitin ligases because of their RING-finger domains. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the posttranslational modification of diverse proteins. Both TRIM29 and ISG15 play both pro-tumoral and anti-tumoral functions in cancer cells derived from different histology. In the current study, we demonstrated that correlation expression of TRIM29 and ISG15 in pancreatic ductal adenocarcinomas (PDACs). The current study demonstrated that TRIM29 knockdown destabilized ISG15 protein via promoting its processing by calpain 3 (CAPN3). Importantly, the current study found that TRIM29 knockdown suppressed cancer stem cell-like features of PDACs, which can be rescued by ISG15 independent of its conjugation function. In addition, the current study demonstrated that extracellular free ISG15 played an important role in maintenance of cancer stem cell-like features of PDACs. Thereby, the current study displayed a novel mechanism by which TRIM29 modulates ISG15 stability via CAPN3-mediated processing, and subsequently extracellular ISG15 maintains the cancer stem cell-like features of PDAC via autocrine mode of action.
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This work was partly supported by National Natural Science Foundation of China (81572828, 81602510, and 81602439) and China Postdoctoral Science Foundation (2017M611286).
Conflict of interest
The authors declare that they have no conflict of interest.
This study was carried out in accordance with the recommendations of Guide for Laboratory Animal Care and Use, Institutional Animal Care and Use Committee of China Medical University. The protocol was approved by the Institutional Animal Care and Use Committee of China Medical University.
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Sun, J., Yan, J., Qiao, HY. et al. Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation. Oncogene 39, 546–559 (2020). https://doi.org/10.1038/s41388-019-0992-2