SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production
Author(s)Emerling, B. M.; Ricoult, S. J. H.; Bell, Eric L.; Guarente, Leonard Pershing
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It has become increasing clear that alterations in cellular metabolism have a key role in the generation and maintenance of cancer. Some of the metabolic changes can be attributed to the activation of oncogenes or loss of tumor suppressors. Here, we show that the mitochondrial sirtuin, SirT3, acts as a tumor suppressor via its ability to suppress reactive oxygen species (ROS) and regulate hypoxia inducible factor 1α (HIF-1α). Primary mouse embryo fibroblasts (MEFs) or tumor cell lines expressing SirT3 short-hairpin RNA exhibit a greater potential to proliferate, and augmented HIF-1α protein stabilization and transcriptional activity in hypoxic conditions. SirT3 knockdown increases tumorigenesis in xenograft models, and this is abolished by giving mice the anti-oxidant N-acetyl cysteine. Moreover, overexpression of SirT3 inhibits stabilization of HIF-1α protein in hypoxia and attenuates increases in HIF-1α transcriptional activity. Critically, overexpression of SirT3 decreases tumorigenesis in xenografts, even when induction of the sirtuin occurs after tumor initiation. These data suggest that SirT3 acts to suppress the growth of tumors, at least in part through its ability to suppress ROS and HIF-1α.
DepartmentMassachusetts Institute of Technology. Department of Biology; Paul F. Glenn Center for Biology of Aging Research (Massachusetts Institute of Technology)
Nature Publishing Group
Bell, E L, B M Emerling, S J H Ricoult, and L Guarente. “SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production.” Oncogene 30, no. 26 (February 28, 2011): 2986-2996. © 2011 Nature Publishing Group
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