Research in the Mostoslavsky’s laboratory aims to decipher the role of chromatin dynamics in cell function, particularly in the context of metabolic adaptations to environmental and nutrient conditions in both health and disease. We focus on the study of a group of proteins called SIRTs, the mammalian homologues of the yeast Sir2. Sir2 is a chromatin silencer that functions as an NAD-dependent histone deacetylase to inhibit DNA transcription and recombination. In the past few years, we have been exploring the crosstalk between epigenetics and metabolism. In particular, our work has focused on the mammalian Sir2 homologue, SIRT6. In recent years, we have identified SIRT6 as a key modulator of metabolism. Mice lacking SIRT6 die from severe metabolic defects, including hypoglycemia and hypoinsulinemia. SIRT6 modulates glucose flux inside the cells, functioning as a histone H3K9 deacetylase to silence glycolytic genes acting as a coexpressor of Hif1alpha, in this way directing glucose away from to reduce intracellular ROS levels (Mostoslavsky et al., Cell 2006; Zhong et al., Cell 2010). Remarkably, we found that SIRT6 acts as a broad tumor suppressor. In colon cancer, SIRT6 functions as a critical inhibitor of the Warburg effect, and cancer cells get rid of SIRT6 to aquire this metabolic switch, providing a long-sought molecular explanation to this phenomenon (Sebastian et al., Cell 2012; Kugel et al., Cell Reports 2015). We have also uncovered key roles for SIRT6 in DNA repair (anchoring the chromatin remodeler SNF2H to DNA breaks)(Toiber et al., Mol Cell 2013) and early development (acting as a repressor of pluripotent genes) in both mouse models and a human syndrome of perinatal lethality, indicating broad biological functions for this chromatin deacetylase (Etchegaray et al., Nat.Cell Biol. 2015; Ferrer et al., Genes & Dev 2018). We also identified SIRT6 as a robust tumor suppressor in pancreatic cancer, where it silences the oncofetal protein Lin28b, protecting against aggressive tumor phenotypes (Kugel et al., Cell 2016). As such, SIRT6 represents an example of a chromatin factor modulated by cancer cells to acquire “epigenetic plasticity”.
Our current studies include exploring the role of SIRT6 in other cancers, deciphering the different stages where metabolic adaptations are established during the process of transformation, understanding the unique adaptations of metastatic cancer cells, and exploring novel metabolic liabilities in cancer.
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