SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect. RNA isolated from brown adipose tissue of SIRT3 WT and KO mice. 5 wild-type samples and 5 SIRT3 KO samples肿瘤细胞表现出异常代谢表型，其特征为即使在氧气充足的条件下仍维持高水平糖酵解。这种被称为瓦伯格效应（Warburg effect）的代谢重编程，可为肿瘤细胞提供生物量合成所需的底物与氧化还原电势。本研究证实，线粒体烟酰胺腺嘌呤二核苷酸（NAD+）依赖性去乙酰化酶SIRT3是瓦伯格效应的关键调控因子。敲除SIRT3可在体内及体外促进符合合成代谢需求的高糖酵解代谢表型。从机制上看，SIRT3不依赖线粒体氧化代谢，而是通过调控缺氧诱导因子1α（HIF1α）——一种控制关键糖酵解酶表达的转录因子——来介导代谢重编程。敲除SIRT3会增加活性氧（ROS）的产生，进而增强HIF1α的稳定性。值得注意的是，40%的人类乳腺癌中存在SIRT3缺失，且其缺失与HIF1α靶基因的上调显著相关。综上，本研究发现，在乳腺癌细胞中过表达SIRT3可直接抑制瓦伯格效应。本研究的RNA样本取自SIRT3野生型（WT）与敲除型（KO）小鼠的棕色脂肪组织，包含5份野生型样本与5份SIRT3敲除型样本。