In the 1920s, the German physiologist Otto Warburg proposed that cancer cells generate energy in ways that are distinct from normal cells. Healthy cells mainly metabolize sugar via respiration in the mitochondria, switching only to glycolysis in the cytoplasm when oxygen levels are low. In contrast, cancer cells rely on glycolysis all the time, even under oxygen-rich scenarios. This shift in how energy is produced—the so-called ‘Warburg effect’, as the observation came to be known—is now recognized as a primary driver of tumor formation, but a mechanistic explanation for the phenomenon has remained elusive.
Now, researchers have implicated a chromatin regulator known as SIRT6 as a key mediator of the switch to glycolysis in cancer cells, a finding that could lead to new therapeutic modalities. “This work is very significant for the cancer field,” says Andrei Seluanov, a cancer biologist at the University of Rochester in New York State who studies SIRT6 but was not involved in the latest study. “It establishes the role of SIRT6 as a tumor suppressor and shows that SIRT6 loss leads to tumor formation in mice and humans.”
SIRT6 encodes one of seven mammalian proteins called sirtuins, a group of histone deacetylases that play a role in regulating metabolism, lifespan and aging. SIRT1—which is activated by resveratrol, a molecule found in the skin of red grapes—is perhaps the best known sirtuin, but several of the others are now the focus of active investigation as therapeutic targets for a range of conditions, from metabolic syndrome to cancer. Just last month, for example, a paper in Nature Medicine demonstrated that SIRT6 plays an important role in heart disease.
Six years ago, a team led by Raul Mostoslavsky, a molecular biologist at the Massachusetts General Hospital Cancer Center in Boston, first showed that SIRT6 protects mice from DNA damage and had anti-aging properties. In 2010, the same team established SIRT6 as a critical regulator of glycolysis. Now, reporting today in Cell, Mostoslavsky and his colleagues have shown that SIRT6 function is lost in cancer cells—thus, definitively establishing SIRT6 as a potent tumor suppressor.
In the latest study, the researchers showed that mouse embryonic cells genetically engineered to lack SIRT6 proliferated much faster than normal cells, growing from 5,000 cells to 200,000 cells in three days. In contrast, SIRT6-expressiong cells grew at less than half that rate over the same time period. When injected into adult mice, these SIRT6-deficient cells also rapidly formed tumors, but this tumor growth was reversed when the scientists put SIRT6 back into the cells.
“Our study provides a proof-of-concept that inhibiting glycolysis in SIRT6-deficient cells and tumors could provide a potential therapeutic approach to combat cancer,” says Mostoslavsky. “Additionally, SIRT6 may be a valuable prognostic biomarker for cancer detection.”
Currently, there are no approved anti-glycolytic drugs against cancer. However, the latest findings indicate that pharmacologically elevating SIRT6 levels might help keep tumor growth at bay. And there’s preliminary data to suggest that the work will translate from the bench to the clinic: looking at a range of cancers from human patients, Mostoslavsky’s team showed that the higher the level of SIRT6 the better the prognosis and the longer the survival times.