SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization

By Lydia W. S. Finley, Arkaitz Carracedo, J. Lee, Amanda L. Souza, Ainara Egia, Jiangwen Zhang, J. Teruya-Feldstein, P. Moreira, S. Cardoso, C. Clish and 2 more. Cancer Cell, 2011

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Summary 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.

Subfields: Cancer Research, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/456fcc422c091fd9654644e5742974de3426e3d5

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Citations in the corpus

Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. (2013, result): “These results reinforce the hypothesis that SIRT3 plays a critical role in mitochondrial metabolic reprogramming toward oxidative metabolism and are consistent with previous reports (Finley et al., 2011).”
Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, background): “, 2010), SIRT3 destabilizes HIF-1a protein (Bell et al., 2011; Finley et al., 2011), and SIRT6 functions as a HIF-1a corepressor (Zhong et al.”
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The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “Loss of SIRT3 has been shown to increase the production of ROS, which leads to stabilization of the protumorigenic transcription factor HIF-1a (41).”
SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways (2013, background): “Acetylation is a major regulator of most or all metabolic pathways in amanner that is conserved from bacteria to mammals (Finley et al., 2011; Hallows et al., 2011; Hebert et al., 2013; Hirschey et al., 2011; Smith et al., 2011; Starai et al., 2002; Wang et al., 2010; Zhang et al., 2009; Zhao et…”
Histone Modifications and Cancer. (2016, background): “Its loss correlates with hypoxia-induced factor (HIF)a stabilization, up-regulation of HIF1a target genes, increased glycolysis, tumor cell proliferation, and fibroblast transformation (Bell et al. 2011), whereas overexpression has the opposite effect (Finley et al. 2011; Sebastian et al. 2012).”
Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “, 2010), and defense against oxidative stress (Finley et al., 2011; Someya et al., 2010); and SIRT6 controls gluconeogenesis (Dominy et al.”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “SIRT1 has tumor suppression activity in ageing- and metabolic syndrome-associated cancer (123, 133, 134, 283), and SIRT3 has also been identified as a tumor suppressor (35, 100, 171, 245).”
SIRT1 and other sirtuins in Metabolism (2013, background): “Upon fasting or calorie restriction, SIRT3 protein level and activity are upregulated in mitochondria [26] to promote fatty acid oxidation via deacetylating long-chainspecific acyl-coenzyme A dehydrogenase (LCAD) [71].”
THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM (2012, neutral): “Importantly, this appears to be specific to SIRT6 because the tumorsuppressive effect of other sirtuins has been observed only in transformed cells (Bell et al., 2011; Fang and Nicholl, 2011; Finley et al., 2011; Kim et al., 2011).”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “SIRT3 orchestrates the metabolism reprogramming via controlling the balance between cytosolic glycolytic metabolism and mitochondrial oxidative metabolism.(222) SIRT3 also plays a regulatory role in proline metabolism via deacetylation of PYCR1.”
Mitochondrial reactive oxygen species and cancer (2014, background): “A survey of human tumors has shown that SirT3 protein expression is significantly decreased in tumors and deletion of at least one copy of SirT3 has been observed in 20%–30% of cancers [78].”