Sci. Aging Knowl. Environ., 9 November 2005
Vol. 2005, Issue 45, p. nf85
[DOI: 10.1126/sageke.2005.45.nf85]

NEWS FOCUS

Cancer Connection

Tumor-fighter throttles life-extending protein SIRT1

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/full/2005/45/nf85

Cancer and long life seem mutually exclusive, but a new study suggests that a life-extending enzyme also hikes tumor risk. Researchers knew that the enzyme, SIRT1, stalls a pathway that causes abnormal cells to commit suicide. The new work pinpoints a protein that normally keeps SIRT1 under control, but whose production wanes with age.

The sirtuin family of enzymes fosters longevity. Cranking up production of these proteins adds time for yeast, worms, and flies. Whether the mammalian sirtuin SIRT1 extends life remains uncertain, but studies indicate that calorie restriction, which promotes longevity, boosts SIRT1 output (see "Low-Cal Connections"). However, some cancer cells also fashion more SIRT1 than do normal cells, hinting that the enzyme abets tumor proliferation. SIRT1 hamstrings the protein p53, which suppresses cancer by prodding cells with damaged DNA to cease dividing or commit suicide (see "Death and Aging, Together at Last"). The protein HIC1 somehow collaborates with p53 to thwart abnormal cell growth, but the gene for HIC1 shuts down in many tumors. To probe the interactions among these proteins, cancer biologist Stephen Baylin of John Hopkins University in Baltimore, Maryland, and colleagues tested whether HIC1 reins in SIRT1.

Using antibodies, the researchers fished HIC1 out of cells engineered to produce extra amounts of both proteins. The procedure also reeled in SIRT1, suggesting that the two proteins congregate. Other experiments showed that HIC1 and SIRT1 glom onto the switch for the SIRT1 gene, presumably adjusting its activity. The team also found that SIRT1 amounts were above normal in cells lacking HIC1. Furthermore, boosting HIC1 output in cells slashed the amount of SIRT1. Together, these results suggest that HIC1 helps curb SIRT1 production. To learn how the proteins affect cellular responses to chromosome damage that can lead to cancer, the team doused cells with a DNA-fracturing compound. Exposure usually spurs cells to kill themselves en masse, but the researchers found that cells lacking HIC1 are more likely to survive. Suicidal behavior returned if the team engineered HIC1-deficient cells to make a faulty version of SIRT1 that interferes with the normal form of the molecule. The findings indicate that HIC1 prevents SIRT1 from stifling cells' suicidal response to DNA injuries. HIC1 normally keeps SIRT1 under wraps, the authors speculate. But previous work showed that as we age, the HIC1 gene accumulates methyl groups that shut it down. Unleashing SIRT1 might help tattered old cells survive, says Baylin, but it could also hike the likelihood that they'll spawn tumors.

The study uncovers a pathway that connects aging and longevity to cancer development, says biochemist John Denu of the University of Wisconsin, Madison. Researchers are hunting for molecules that boost SIRT1 activity, and they've already identified one such compound from red wine that prolongs life in worms and flies (see "Resveratrol to the Rescue"). Scientists don't have enough evidence to conclude that this strategy is hazardous, says molecular biologist Shin-Ichiro Imai of Washington University in St. Louis, Missouri. SIRT1 exerts widespread effects on metabolism--such as adjusting insulin release--that might counteract its cancer-promoting impact on cells, he says. Moreover, calorie-restricted rodents are less susceptible to cancer despite increased amounts of SIRT1, says molecular biologist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge. The new results might help humans exploit the positive side of SIRT1, allowing us to live longer without inviting cancer.


November 9, 2005
  1. W. Y. Chen et al., Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437-448 (2005). doi:10.1016/j.cell.2005.08.011 [CrossRef][Medline]
Citation: M. Leslie, Cancer Connection. Sci. Aging Knowl. Environ. 2005 (45), nf85 (2005).








Science of Aging Knowledge Environment. ISSN 1539-6150