SIRT3 通过使 HIF1α 不稳定来抵制癌细胞代谢的重编程。
SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
机构信息
Department of Pathology, The Paul F. Glenn Labs for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2011 Mar 8;19(3):416-28. doi: 10.1016/j.ccr.2011.02.014.
Abstract
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 required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.
摘要
肿瘤细胞表现出异常的代谢特征，即使在有氧气的情况下，糖酵解也很高。这种代谢重编程被称为瓦伯格效应，为肿瘤细胞提供了生成生物量所需的底物。在这里，我们表明线粒体 NAD 依赖性去乙酰化酶 SIRT3 是瓦伯格效应的关键调节因子。从机制上讲，SIRT3 通过使缺氧诱导因子-1α（HIF1α）失稳来介导代谢重编程，HIF1α 是控制糖酵解基因表达的转录因子。SIRT3 的缺失会增加活性氧的产生，导致 HIF1α 的稳定。人乳腺癌中 SIRT3 的表达减少，其缺失与 HIF1α 靶基因的上调相关。最后，我们发现 SIRT3 的过表达抑制乳腺癌细胞的糖酵解和增殖，为肿瘤抑制提供了一种代谢机制。
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