Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China.
Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110122, China.
Biochim Biophys Acta Mol Cell Res. 2019 May;1866(5):819-827. doi: 10.1016/j.bbamcr.2019.02.008. Epub 2019 Feb 14.
BAG3 is a member of the cochaperone BAG family and often highly expressed in various cancers. Recently, evidences show that BAG3 promotes stemness of human cancer cells. IFN-stimulated genes 15 (ISG15) is an ubiquitin-like molecule, which is covalently conjugated with substrates to form ISGylated proteins. Global screening BAG3 interacting partners demonstrated that ISG15 might be a potential binding partner. The current study revealed that BAG3 did not interact with ISG15, but positively regulated ISG15 expression in pancreatic ductal adenocarcinoma cancer (PDAC). It was further found that BAG3 deletion stabilized ISG15 mRNAs, while suppressed its translation via increasing Serine phosphorylation of Ago2 at position 387 (S387). Both BAG3 deletion and ISG15 knockdown suppressed stem cell-like phenotypes of PDAC cells, including clonogenicity, invasiveness and spheroid formation. In addition, ectopic ISG15 expression rescued the suppressive role of BAG3 deletion in cancer stem cell (CSC)-like phenotypes of PDAC cells, and this effect of ISG15 was independent of its ISGylation function. The current study implies that BAG3 and ISG15 may provide a therapeutic advantage for PDAC.
BAG3 是伴侣蛋白 BAG 家族的成员，通常在各种癌症中高度表达。最近的证据表明，BAG3 促进了人类癌细胞的干性。干扰素刺激基因 15（ISG15）是一种泛素样分子，它与底物发生共价结合形成 ISG 化蛋白。对 BAG3 相互作用伙伴的全面筛选表明，ISG15 可能是一个潜在的结合伙伴。本研究揭示了 BAG3 与 ISG15 不相互作用，但在胰腺导管腺癌（PDAC）中正向调节 ISG15 的表达。进一步发现，BAG3 缺失稳定了 ISG15 mRNA，同时通过增加 Ago2 位置 387（S387）的丝氨酸磷酸化来抑制其翻译。BAG3 缺失和 ISG15 敲低均抑制了 PDAC 细胞的干细胞样表型，包括克隆形成能力、侵袭性和球体形成。此外，外源性 ISG15 表达挽救了 BAG3 缺失对 PDAC 细胞癌干细胞（CSC）样表型的抑制作用，而 ISG15 的这种作用与其 ISG 化功能无关。本研究表明，BAG3 和 ISG15 可能为 PDAC 提供治疗优势。
