BAG3 deletion suppresses stem cell-like features of pancreatic ductal adenocarcinoma via translational suppression of ISG15
BAG3 deletion suppresses stem cell-like features of pancreatic ductal adenocarcinoma via translational suppression of ISG15
复制标题
BAG3 缺失通过 ISG15 的翻译抑制抑制胰腺导管腺癌的干细胞样特征
DOI：
10.1016/j.bbamcr.2019.02.008
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发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Wang, Hua-Qin
中科院分区：
文献类型：
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作者：
Li, Xin-Yu;Yan, Jing;Wang, Hua-Qin
BAG3是cochaperone BAG家族的成员，在各种癌症中经常高表达。最近，有证据表明BAG3能促进人类癌细胞的生长。ifn刺激基因15 （ISG15）是一种泛素样分子，它与底物共价结合形成isgated蛋白。全球筛选BAG3相互作用伙伴表明ISG15可能是潜在的结合伙伴。目前的研究表明，BAG3不与ISG15相互作用，但正向调节ISG15在胰腺导管腺癌（pancreatic ductal adenocarcinoma cancer， PDAC）中的表达。进一步发现BAG3缺失稳定了ISG15 mrna，同时通过增加387位Ago2的丝氨酸磷酸化来抑制其翻译（S387）。BAG3缺失和ISG15敲低均可抑制PDAC细胞的干细胞样表型，包括克隆性、侵袭性和球状体形成。此外，异位ISG15表达恢复了BAG3缺失对PDAC细胞癌梢细胞（CSC）样表型的抑制作用，并且ISG15的这种作用独立于其isg酰化功能。目前的研究表明BAG3和ISG15可能为PDAC提供治疗优势。
BAG3 is a member of the cochaperone BAG family and often highly expressed in various cancers. Recently, evidences show that BAG3 promotes sternness 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 stern 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.