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Metabolism in 'the driver's seat

It is increasingly accepted that metabolic changes in cancer cells can drive tumour formation. The finding that the SIRT6 protein suppresses tumour formation by regulating metabolism adds weight to this view.

Cancer development is accompanied by extensive reprogramming of cellular energy metabolism1. A cancer-associated metabolic switch, called the Warburg effect, activates glycolysis — a biochemical pathway that fuels tumour growth by supporting the high energetic and biosynthetic demands of cancer cells. Growing evidence suggests that flipping the switch back, away from glycolysis, could be an effective strategy for tumour suppression. Writing in Cell, Sebastián et al.2 provide further support for this idea. They show that the protein SIRT6 prevents tumorigenesis by opposing cancer-promoting metabolic programs. Intriguingly, SIRT6 is not a classic metabolic enzyme, but rather a protein that regulates the integrity and proper expression of the genome3. Sebastián and colleagues propose that, through gene regulation, SIRT6 controls a key metabolic node that could be targeted to combat cancer.

Tumour initiation and progression involves multiple steps during which cells acquire several hallmarks of cancer, including resistance to cell death and evasion of growth-suppressive cues, that allow them to bypass normal checks on cell proliferation4. Much work on cultured cells has shown that several cellular pathways must be deregulated5 for cells to become tumorigenic. For example, in mouse embryonic fibroblasts (MEFs), inactivation of a single tumour suppressor can cause cellular immortalization — the characteristic ability of cancer cells to divide without limit. But these immortalized cells are not cancerous and do not form tumours when transplanted into mice, unless additional tumour-suppressive or oncogenic pathways are deregulated.

Sebastián et al. find that SIRT6 deficiency provides the additional 'hit' required to transform immortalized MEFs into proper cancer cells. They also report that in cancer cells, and in a mouse model of colorectal cancer, SIRT6 deficiency increases tumour formation. Thus, SIRT6 loss may promote both cancer initiation and cancer progression (Fig. 1). These findings fit well with previous discoveries that SIRT6 opposes liver-cancer initiation6 and controls multiple potentially tumour-suppressive pathways3.

Figure 1: On the road to cancer.

For a normal cell to become cancerous, it must not only become immortal, acquiring the ability to divide indefinitely by escaping cellular checkpoints, but also undergo further oncogenic modifications. The cancer cells can then give rise to tumours. Sebastián et al.2 report that the protein SIRT6 can prevent both cancer initiation and cancer progression by suppressing the cancer-associated metabolic processes of glycolysis and protein synthesis. Other previously known roles of SIRT6 suggest that the protein could also contribute to tumour suppression at other stages of cancer development (dashed lines).

Analysis of human-tumour databases helped Sebastián and co-authors to validate the idea that SIRT6 is an authentic tumour suppressor. They found frequent deletions of the SIRT6 gene and reductions in its messenger RNA levels in pancreatic and colorectal tumour samples, and showed that low levels of SIRT6 are associated with poor patient outcomes. These findings have clinical implications: SIRT6 expression could serve as a biomarker for cancer prognosis, and SIRT6-activating compounds might be powerful drugs. Indeed, several features of SIRT6 make it an especially promising pharmacological target. In particular, it is a highly selective enzyme that removes acetyl groups from only a few proteins3, and its known cellular functions are all consistent with beneficial effects in the context of cancer. Therapeutic activation of SIRT6 might therefore have fewer unwanted effects than modulating the activity of more promiscuous enzymes.

There is growing evidence that tumour suppressors often control several aspects of cancer biology, and SIRT6 is no exception3 (Fig. 1). It prevents chromosome breakage and abnormal rejoining, and promotes DNA repair — activities that protect against mutations that can fuel tumour progression. It also regulates gene-expression programs that have roles in cancer. For instance, it prevents excessive gene activation by NF-κB — a transcription factor that promotes cell proliferation, resistance to cell-death signals, and metabolic and inflammatory processes that favour tumour initiation and growth. Sebastián et al. report yet another tumour-suppressing effect of SIRT6: it limits the expression of genes that are involved in protein synthesis and which are activated by the MYC oncogene to support tumour growth.

Despite these and other possible tumour-suppressive mechanisms of SIRT6 action, the researchers propose that it is the metabolic rewiring triggered by inactivation of this protein that is essential to making cells cancerous. Indeed, SIRT6 is known to oppose gene activation by HIF1, a transcription factor that activates key enzymes of glycolysis and increases glucose uptake into cells. The authors also show that reversing the increased glycolysis in cancerous SIRT6-deficient cells — by inactivating a central glycolytic enzyme or by reintroducing SIRT6 — reduces the cells' tumorigenic potential.

Sebastián and colleagues further propose that even without any other oncogenic changes, increased glycolytic metabolism due to SIRT6 loss is sufficient for tumour initiation. That a single genetic change is enough to transform normal cells into tumour cells would be a remarkable exception to the rule that combined deregulation of several pathways is required for oncogenic transformation. If proven, this could indicate that metabolic change associated with SIRT6 loss supplies a more powerful oncogenic drive than most other known cancer-promoting mutations.

Alternatively, other effects of SIRT6 loss on tumour-suppressive pathways could favour early steps in cancer development. Future work should ask how various functions of SIRT6 contribute to cancer prevention, and how these intersect with cellular metabolic control. It should also be determined whether SIRT6 loss causes spontaneous tumour formation in animals. A study7 this year evaluated SIRT6-deficient mice up to 17 months of age and, surprisingly, found no evidence of tumour formation. Although the number of mice investigated was small, this observation seems to be at odds with the strong tumorigenic potential of SIRT6-deficient cells that Sebastián et al. describe. Studying cancer development in larger cohorts of SIRT6-deficient mice is necessary to resolve this issue.

What molecular mechanisms underlie the observed metabolic changes in SIRT6-deficient cells? Both the HIF1 and MYC pathways have central roles in the metabolic reprogramming of cancer cells, and NF-κB signalling and genomic instability can also promote glycolytic metabolism1,6. Perhaps SIRT6 prevents metabolic rewiring in cancer through several pathways, which might be redundant or operate in specific cell types or physiological contexts.

Sebastián and collaborators propose that inhibition of glycolytic metabolism could be used to treat tumours that have low SIRT6 levels. Perhaps equally exciting is the prospect that activation of SIRT6 might be beneficial even in tumours that arise independently of changes in SIRT6. If increasing the amount or activity of SIRT6 can indeed reduce the tumorigenicity of cells transformed by other oncogenic manipulations, strategies involving SIRT6 activation could eventually be widely used for tumour suppression. It is noteworthy that SIRT6 attenuates ageing-related cellular processes, and increasing its activity in mice can extend lifespan3,8. So SIRT6 activation might not only provide an anticancer strategy, but also serve as a preventive medical intervention throughout life.


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Correspondence to Katrin F. Chua.

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Tasselli, L., Chua, K. Metabolism in 'the driver's seat. Nature 492, 362–363 (2012).

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