Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation
Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation
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TRIM29 的缺失通过加速 ISG15 降解抑制 PDAC 的癌症干细胞样特征
DOI：
10.1038/s41388-019-0992-2
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发表时间：
2020-01-01
期刊：
影响因子：
8
通讯作者：
Wang, Hua-Qin
中科院分区：
文献类型：
--
作者：
Sun, Jia;Yan, Jing;Wang, Hua-Qin
TRIM 家族蛋白因其环指结构域而被定义为 E3 泛素连接酶。泛素样蛋白干扰素刺激基因 15 (ISG15) 编码一种 15 kDa 的蛋白，该蛋白参与多种蛋白的翻译后修饰。 TRIM29 和 ISG15 在不同组织学来源的癌细胞中都发挥促肿瘤和抗肿瘤功能。在当前的研究中，我们证明了 TRIM29 和 ISG15 在胰腺导管腺癌 (PDAC) 中的相关表达。目前的研究表明，TRIM29 敲低通过促进钙蛋白酶 3 (CAPN3) 的加工来破坏 ISG15 蛋白的稳定性。重要的是，当前的研究发现 TRIM29 敲低抑制了 PDAC 的癌症干细胞样特征，而 ISG15 可以独立于其缀合功能来挽救这种特征。此外，目前的研究表明，细胞外游离ISG15在维持PDAC的癌症干细胞样特征方面发挥着重要作用。因此，当前的研究展示了一种新机制，TRIM29通过CAPN3介导的加工调节ISG15稳定性，随后细胞外ISG15通过自分泌作用模式维持PDAC的癌症干细胞样特征。
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.