Tumorigenic Role for Cancer Metabolism

Science Signaling  11 Dec 2012:
Vol. 5, Issue 254, pp. ec323
DOI: 10.1126/scisignal.2003860

To support their increased proliferative rate compared with that of untransformed cells, tumor cells change their metabolism so that they break down glucose completely by glycolysis (to form lactate) rather than by oxidative phosphorylation. Many of the oncogenes that cause tumorigenesis, such as those affecting growth factor receptor signaling components, also affect cellular metabolism. Thus, it has been difficult to determine the contribution of the metabolic state of tumor cells to their tumorigenicity (see commentary by Lyssiotis and Cantley). Sebastián et al. investigated a role for the NAD-dependent histone deacetylase SIRT6, which is a transcriptional repressor of genes whose products mediate glycolysis. Mouse embryonic fibroblasts (MEFs) from SIRT6 knockout (SIRT6 KO) mice exhibited increased glucose uptake, lactate production, and anchor-independent growth compared with wild-type MEFs, and these effects were reversed by expression of wild-type SIRT6 but not a catalytically inactive mutant SIRT6. Western blotting analysis showed that loss of SIRT6 did not lead to an increase in the activation of molecules downstream of growth factor receptors. SIRT6 KO MEFs transformed with oncogenic mutations in Ras and p53 produced larger tumors than did transformed wild-type MEFs, and the SIRT6 KO tumors had increased glycolytic activity as determined by PET scans. In addition, loss of SIRT6 alone in the absence of oncogenic mutations led to tumor formation. Knockdown of an enzyme critical for glycolysis suppressed the tumorigenicity of SIRT6 KO cells in vivo. Chromatin immunoprecipitation assays and sequencing showed that SIRT6 associated with the transcription factor Myc at the promoters of a subset of Myc target genes, including ribosomal genes, and SIRT6 repressed the expression of these genes. Knockdown of Myc in SIRT6 KO MEFs reduced their proliferation and led to decreased tumor growth. Analysis of various human tumors showed that the Sirt6 locus was lost in various human cancers, and reduced expression of Sirt6 correlated with a poorer prognosis. Together, these data suggest that SIRT6 acts as a tumor suppressor by suppressing glycolytic metabolism and that loss of this control of cancer metabolism promotes tumorigenesis.

C. Sebastián, B. M. M. Zwaans, D. M. Silberman, M. Gymrek, A. Goren, L. Zhong, O. Ram, J. Truelove, A. R. Guimaraes, D. Toiber, C. Cosentino, J. K. Greenson, A. I. MacDonald, L. McGlynn, F. Maxwell, J. Edwards, S. Giacosa, E. Guccione, R. Weissleder, B. E. Bernstein, A. Regev, P. G. Shiels, D. B. Lombard, R. Mostoslavsky, The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185–1199 (2012). [Online Journal]

C. A. Lyssiotis, L. C. Cantley, SIRT6 puts cancer metabolism in the driver’s seat. Cell 151, 1155–1156 (2012). [Online Journal]