SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production

Abstract

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.

Sirtuin-7 Inhibits the Activity of Hypoxia-inducible Factors

“…Co-immunoprecipitation experiments demonstrated that Myc epitope-tagged Sirt6 interacted with coexpressed FLAG epitope-tagged HIF-1␣ (Fig. 1A), which was consistent with a recent report (29) and served as a positive control. Myc-tagged Sirt5 did not interact with FLAG-HIF-1␣ or HIF-2␣, but interaction of Myc-tagged Sirt7 with both FLAG-HIF-1␣ (Fig.…”

“…Sirt6 knock-out mice develop lethal hypoglycemia early in life, which is due to the role of Sirt6 as a co-repressor of HIF-1 target genes (28). Finally, Sirt3, which is a mitochondrial deacetylase, may regulate HIF-1 signaling in cancer cell lines (29,30) by an indirect effect on mitochondrial reactive oxygen species.…”

NAD + and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

“…The physiological targets of SIRT3 include over 100 mitochondrial proteins, including diverse proteins that suppress ROS generation (40). Acetylation of these proteins typically leads to increased ROS production, whereas SIRT3-mediated deacetylation leads to decreased ROS levels (41)(42)(43). Indeed, treatment of MCF-7 cells with NAD + reduced the increase in ROS induced by vinblastine (Fig.…”

From Sirtuin Biology to Human Diseases: An Update

“…Although differentiated cells under normal conditions obtain energy by oxidizing fuels such as glucose through mitochondrial oxidative phosphorylation, Warburg observed that rapidly proliferating cancer cells often up-regulate glycolysis, which we now understand allows cells to generate macromolecules needed for cellular proliferation. Recent studies reported that SIRT3 normally counteracts this metabolic switch by destabilizing HIF-1␣ through down-regulation of ROS (52,53). Overexpressing SIRT3 also suppresses the Warburg effect in various cancer cell lines lacking SIRT3 (52,53), suggesting that SIRT3 may be a tumor suppressor.…”