SIRT6 suppresses tumor initiation and growth by inhibiting cancer cell metabolic reprogramming.
Major finding: SIRT6 suppresses tumor initiation and growth by inhibiting cancer cell metabolic reprogramming.
Mechanism: SIRT6 represses aerobic glycolysis and MYC-dependent ribosomal gene expression.
Impact: Decreased levels of SIRT6 are observed in human cancers and are associated with tumor relapse.
To maintain high proliferation rates, cancer cells increase glucose uptake and switch from mitochondrial respiration to aerobic glycolysis, a phenomenon known as the Warburg effect. However, the factors that mediate this switch and whether this metabolic reprogramming can facilitate tumorigenesis are unclear. Sebastián and colleagues hypothesized that Sirtuin 6 (SIRT6), an NAD+-dependent protein deacetylase that inhibits aerobic glycolysis, protects against tumor growth. Consistent with this possibility, loss of Sirt6 conferred a growth advantage and was sufficient to induce tumor formation, even by nontransformed mouse embryonic fibroblasts (MEF), without activation of oncogenic signaling. Sirt6-deficient MEFs and tumors exhibited enhanced glucose uptake and lactate production and increased expression of glycolytic genes, indicative of a switch to aerobic glycolysis. Inhibition of glycolysis via downregulation of pyruvate dehydrogenase kinase 1 (PDK1) abrogated tumorigenesis, indicating that SIRT6 suppresses tumor formation by repressing glycolytic reprogramming necessary for cancer cell proliferation. Furthermore, SIRT6 interacted with and repressed the activity of MYC at the promoters of ribosomal protein genes, suggesting that SIRT6 also blocks cancer cell proliferation by inhibiting ribosome biosynthesis. Indeed, elevated levels of ribosomal gene expression were detected in Sirt6-deficient tumors, and simultaneous depletion of MYC reduced the expression of these ribosomal genes and diminished tumor growth. Conditional deletion of Sirt6 in the Apcmin colon cancer model augmented tumor formation and invasiveness, whereas treatment of these mice with a PDK1 inhibitor impaired tumorigenesis. Moreover, downregulation of SIRT6 was detected in human cancer samples, particularly in pancreatic and colorectal tumors, including early premalignant lesions, and was associated with increased disease relapse in patients with aggressive tumors. These results demonstrate that SIRT6 suppresses both tumor initiation and progression by regulating cancer metabolism and suggest inhibition of this deacetylase as a potential therapeutic strategy.