May 9, 2012
Enzyme SIRT7 Sabotages Tumor Suppressor Network In Cells
When collaborators led by those at Baylor College of Medicine and Stanford University School of Medicine sought to unravel the mysterious role of the enzyme SIRT7 in the cell, they discovered a saboteur that uses other molecules to maintain tumor cells in their cancer state, suppressing the systems that are supposed to prevent that malignant transformation. A report on their work appears online today in the journal Nature.
"This is a very bad gene," said Dr. Wei Li, associate professor in the NCI-designated Dan L. Duncan Cancer Center at BCM and a corresponding author of the report. "When you get rid of the gene, you reduce tumor growth."
How the gene works
Collaborating with Dr. Katrin Chua, assistant professor of medicine at Stanford, and members of her laboratory, Li and his laboratory teamed up to understand how the gene works. In the first experiment, they used a technique called genome-wide Chromatin Immunoprecipitation Sequencing (ChIP-Seq) to find out where the gene binds to the genome. Chua's laboratory did most of the bench lab experiments, and Li's lab carried out the bioinformatics or computational analysis.
Using a program that Li co-developed called MACS, they found that the targets of the genes were areas of the genome involved in gene translation and the activity of tumor suppressor genes.
Further analysis showed that SIRT7 removes acetylated lysine 18 from histone H3. Histones are proteins that help package the DNA helix. This process enabled SIRT7 to repress transcription of DNA into RNA, an important part of making proteins. When the protein from a tumor suppressor gene exists in reduced quantities, it has less ability to stop tumor formation.
Tumor growth stalls
"We found that this deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells," said the authors in their report.
To accomplish this, SIRT7 recruits another molecule — ELK 4 — to target its effects to a specific tumor suppressor gene, said Li. When SIRT7 is removed from a cell, tumor growth stalls, he said. SIRT7 actually binds to the chromatin — part of a complex of DNA and protein that makes up the chromosomes — making it difficult for the gene to express itself as a protein.
Others who took part in this work include Yuanxin Xi (one of three first authors) and Kaifu Chen of BCM, Matthew F. Barber and Eriko Michishita (two first authors), Luisa Tasselli, Mitomu Kioi, Ruth Tennen, Silvana Paredes and Or Gozani of Stanford; Zarmik Moqtaderi and Kevin Struhl of Harvard Medical School and Tufts Medical Center in Boston; Nicolas L. Young and Benjamin Garcia of Princeton University in New Jersey.
Funding for this work came from the National Institutes of Health, the National Science Foundation, the U.S. Department of Defense, the Cancer Prevention and Research Institute of Texas, the U.S. Department of Veterans Affairs, the American Italian Cancer Foundation, the ARCS (Achievement Awards for College Scientists) Foundation, the Mason Case Fellowship program, the Paul B. Beeson Career Development Awards in Aging Research Program, the Ellison Medical Foundation and the Dan L. Duncan Family Foundation.
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