BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in 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.

有氧糖酵解，即历史上所称的瓦伯格效应（Warburg effect），是癌细胞的标志性特征之一。本研究解析了BAG3在胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）细胞有氧糖酵解中的作用及其分子机制。本研究数据显示，BAG3的异常表达可显著驱动胰腺导管腺癌细胞的糖代谢重编程。机制层面，BAG3可在转录后水平上调糖酵解首步关键酶——己糖激酶2（Hexokinase 2, HK2）的表达。BAG3可与HK2 mRNA结合，且其表达水平会改变RNA结合蛋白Roquin与IMP3在HK2 mRNA上的招募程度。敲低BAG3可通过促进Roquin的招募以降低HK2 mRNA的稳定性；而过表达BAG3则通过促进IMP3的招募以增强HK2 mRNA的稳定性。综上，本研究结果表明，BAG3可通过与HK2 mRNA结合促进胰腺导管腺癌细胞的糖代谢重编程，这提示BAG3或可成为靶向有氧糖酵解通路开发新型抗癌制剂的潜在靶点。