Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer.

Epithelial-mesenchymal transition (EMT) enhances invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We showed that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecules biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and ROS production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with TCF. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.

上皮 - 间质转化（EMT）增强侵袭性，并赋予肿瘤细胞癌干细胞（CSC）样特性。我们发现，对E - 钙黏蛋白启动子沉默至关重要的Snail - G9a - Dnmt1复合物，在基底样乳腺癌（BLBC）中对果糖 - 1,6 - 二磷酸酶（FBP1）的启动子甲基化也是必需的。FBP1缺失诱导糖酵解，导致葡萄糖摄取增加、大分子生物合成增加、四聚体PKM2形成以及在缺氧条件下维持ATP产生。FBP1缺失还通过抑制线粒体复合物I活性抑制氧消耗和活性氧（ROS）产生；这种代谢重编程通过增强β - 连环蛋白与TCF的相互作用，导致CSC样特性和致瘤性增加。我们的研究表明，FBP1缺失是EMT和BLBC中的一个关键致癌事件。