BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.
BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.
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BAG3 直接稳定己糖激酶 2 mRNA 并促进胰腺癌细胞中的有氧糖酵解
DOI：
10.1083/jcb.201701064
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Wang HQ
中科院分区：
文献类型：
--
作者：
An MX;Li S;Yao HB;Li C;Wang JM;Sun J;Li XY;Meng XN;Wang HQ
癌细胞经常表现出有氧糖酵解，也就是众所周知的沃堡效应。An等人。确定BAG3的一种新的RNA调节活性，BAG3是一种与多种癌症有关的蛋白质。BAG3在转录后增强了糖酵解的第一种酶己糖激酶2的表达，并对胰腺癌细胞的葡萄糖代谢进行了重新编程。有氧糖酵解，一种历史上被称为华宝效应的现象，是癌细胞的标志之一。在本研究中，我们研究了BAG3在胰腺导管腺癌(PDAC)有氧糖酵解中的作用及其分子机制。我们的数据表明，BAG3的异常表达显著促进了PDAC细胞中葡萄糖代谢的重新编程。机制上，BAG3在转录后水平增加了糖酵解的第一个关键酶-己糖激酶2(HK2)的表达。BAG3与HK2mRNA相互作用，BAG3的表达程度改变了RNA结合蛋白Roquin和IMP3对HK2mRNA的募集。BAG3基因敲除通过促进Roquin募集而使HK2mRNA不稳定，而BAG3过表达则通过促进IMP3募集而稳定HK2mRNA。总之，我们的结果表明，BAG3通过与HK2 mRNA相互作用促进PDAC细胞中葡萄糖代谢的重编程，提示BAG3可能是开发新型抗癌药物的有氧糖酵解途径中的一个潜在靶点。
Cancer cells frequently exhibit aerobic glycolysis, known as the Warburg effect. An et al. identify a novel RNA regulatory activity of BAG3, a protein implicated in various cancers. BAG3 enhances posttranscriptionally the expression of Hexokinase 2, the first enzyme involved in glycolysis, and it reprograms glucose metabolism by pancreatic cancer cells. Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.
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