Dott. Carlos Sebastian
- Italian Institute of Genomic Medicine (IIGM)
Strada Provinciale 142, km 3.95, 10060, Candiolo (TO), IT
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Our laboratory has described SIRT6 as a potent tumor suppressor that epigenetically controls cancer metabolism (Sebastian et al., Cell 2012). SIRT6 is a member of the conserved Sirtuin family of histone deacetylases that integrate metabolic networks with cellular growth responses, and have been implicated in the control of aging, genomic stability, cellular responses to stress, metabolism and cancer. Via its H3K9/K56 deacetylase activity, SIRT6 co-represses Hif1α and MYC in cancer cells, directly regulating the expression of key glycolytic and ribosomal protein genes. Importantly, loss of this tumor suppressor promotes a robust metabolic reprogramming that is sufficient to drive tumorigenesis, bypassing major oncogenic signaling pathway activation. Furthermore, inhibition of glycolysis by genetic or chemical means abrogates the tumorigenic potential of SIRT6-deficient cells, highlighting a dominant and driving role of glucose metabolism reprogramming in tumor initiation. Indeed, our preliminary results suggest a role for SIRT6 in regulating the number and activity of tumor-initiating cells by controlling glucose metabolism. Together, these findings represent one of very few direct demonstrations of the centrality of tumor metabolism to the process of cancer initiation and growth.