Mice without the pro-longevity gene SIRT6 had higher risk of gastrointestinal cancers
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Loss of the SIRT6 protein in mice increases the number, size and aggressiveness of tumors, according to the new research published in the scientific journal Cell. The study also suggests that the loss of SIRT6 promotes tumor growth in human colon and pancreatic cancers.
"It is critical to understand the spectrum of genes that suppress tumor development," says co-senior author David Lombard, M.D., Ph.D., assistant professor of pathology and assistant research professor at the U-M Institute of Gerontology at the U-M Medical School.
"Our research suggests SIRT6 may have a critical role in blocking cancer and controlling cellular metabolism. We hope to build on this work to better understand how this protein suppresses tumor development, and provide insight into potential future means of reprogramming cancer metabolism."
The research was done in conjunction with the Massachusetts General Hospital Cancer Center at Harvard Medical School. Raul Mostoslavsky, M.D., Ph.D., assistant professor of medicine at Harvard Medical School, was the co-senior author.
The new research highlights the role SIRT6 plays in dampening cancer growth by repressing aerobic glycolysis a major feature of cancer cells that involves the conversion of glucose to lactate. SIRT6 also inhibits activity of the key cancer gene Myc.
Many studies in cancer biology have focused on the importance of tumor suppressor proteins and how they may protect cells from progressing to cancer.
The new research follows up on previous studies that have tied SIRT6 to longevity in male mice. Other research has also shown that the protein may protect against diet-induced obesity.
"This work points to the conservation of biological mechanisms between lower organisms and humans, and the importance of fundamental basic research," says Lombard, a researcher at the U-M Comprehensive Cancer Center. "This family of proteins was originally studied in yeast. It turns out to have key roles in promoting mammalian health."
Additional authors: Bernadette Zwaans, graduate student research assistant in pathology, and Joel Greenson, professor of pathology, both of U-M. Other authors were Carlos Sebastiá, Dafne M. Silberman, Melissa Gymrek, Alon Goren, Lei Zhong, Oren Ram, Jessica Truelove, Alexander R. Guimaraes, Debra Toiber, Claudia Cosentino, Alasdair I. MacDonald, Liane McGlynn, Fraser Maxwell, Joanne Edwards, Sofia Giacosa, Ernesto Guccione, Ralph Weissleder, Bradley E. Bernstein, Aviv Regev, Paul G. Shiels.
Funding: National Institutes of Health (Awards GM093072-01, DK088190-01A1 and GM101171); University of Michigan Comprehensive Cancer Center, Ellison Medical Foundation, Pardee Foundation, Sidney Kimmel Cancer Research Foundation.
Conflict of Interest: Mostoslavsky is a member of the Scientific Advisory Board of Sirtris, a company that is attempting to develop sirtuin-directed therapeutics.
Reference: Sebastián et al., Cell, "The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism," Dec.7, 2012, http://dx.doi.org/10.1016/j.cell.2012.10.047.