Jeong S M, Lee J, Finley L W S, Schmidt P J, Fleming M D, Haigis M C
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Oncogene. 2015 Apr 16;34(16):2115-24. doi: 10.1038/onc.2014.124. Epub 2014 Jun 9.
Iron metabolism is essential for many cellular processes, including oxygen transport, respiration and DNA synthesis, and many cancer cells exhibit dysregulation in iron metabolism. Maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which control the expression of iron-related genes by binding iron-responsive elements (IREs) of target mRNAs. Here, we report that mitochondrial SIRT3 regulates cellular iron metabolism by modulating IRP1 activity. SIRT3 loss increases reactive oxygen species production, leading to elevated IRP1 binding to IREs. As a consequence, IRP1 target genes, such as the transferrin receptor (TfR1), a membrane-associated glycoprotein critical for iron uptake and cell proliferation, are controlled by SIRT3. Importantly, SIRT3 deficiency results in a defect in cellular iron homeostasis. SIRT3 null cells contain high levels of iron and lose iron-dependent TfR1 regulation. Moreover, SIRT3 null mice exhibit higher levels of iron and TfR1 expression in the pancreas. We found that the regulation of iron uptake and TfR1 expression contribute to the tumor-suppressive activity of SIRT3. Indeed, SIRT3 expression is negatively correlated with TfR1 expression in human pancreatic cancers. SIRT3 overexpression decreases TfR1 expression by inhibiting IRP1 and represses proliferation in pancreatic cancer cells. Our data uncover a novel role of SIRT3 in cellular iron metabolism through IRP1 regulation and suggest that SIRT3 functions as a tumor suppressor, in part, by modulating cellular iron metabolism.
铁代谢对许多细胞过程至关重要，包括氧气运输、呼吸作用和DNA合成，并且许多癌细胞在铁代谢方面表现出失调。细胞铁稳态的维持由铁调节蛋白（IRPs）调控，这些蛋白通过结合靶mRNA的铁反应元件（IREs）来控制铁相关基因的表达。在此，我们报告线粒体SIRT3通过调节IRP1活性来调控细胞铁代谢。SIRT3缺失会增加活性氧的产生，导致IRP1与IREs的结合增加。因此，IRP1的靶基因，如转铁蛋白受体（TfR1），一种对铁摄取和细胞增殖至关重要的膜相关糖蛋白，受SIRT3调控。重要的是，SIRT3缺陷导致细胞铁稳态出现缺陷。SIRT3缺失的细胞含有高水平的铁，并且失去了铁依赖性的TfR1调控。此外，SIRT3缺失的小鼠胰腺中铁和TfR1的表达水平更高。我们发现铁摄取和TfR1表达的调控有助于SIRT3的肿瘤抑制活性。实际上，在人类胰腺癌中，SIRT3表达与TfR1表达呈负相关。SIRT3过表达通过抑制IRP1降低TfR1表达，并抑制胰腺癌细胞的增殖。我们的数据揭示了SIRT3通过调节IRP1在细胞铁代谢中的新作用，并表明SIRT3部分地通过调节细胞铁代谢发挥肿瘤抑制作用。
