Chromatin packaging helps decipher how cancer develops
Minority children awaiting a donor heart for transplant have a higher death rate than white children, even after controlling for clinical risk factors, according to research presented at the American Heart Association’s Scientific Sessions 2008. In a study conducted by researchers in Boston, waitlist mortality was 14 percent for white children, 19 percent for black,
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To decipher how cancer develops, Johns Hopkins Kimmel Cancer Center investigators say researchers must take a closer look at the packaging.
Specifically, their findings in the December 2, 2008, issue of PLoS Biology point to the three dimensional chromatin packaging around genes formed by tight, rosette-like loops of Polycomb group proteins (PcG). The chromatin packaging, a complex combination of DNA and proteins that compress DNA to fit inside cells, provides a repressive hub that keeps genes in a low expression state.
“We think the polycomb proteins combine with abnormal DNA methylation of genes to deactivate tumor suppressor genes and lock cancer cells in a primitive state,” says Stephen B. Baylin, M.D., Virginia and D.K. Ludwig Professor of Oncology and senior author.
Prior to this discovery, investigators studying cancer genes, looked at gene silencing as a linear process across the DNA, as if genes were flat, one dimensional objects. Research did not take into account the way genes are packaged.
To better understand the role of the PcG packaging, the team compared embryonic cells to adult colon cancer cells. The gene studied in the embryonic cells was packaged by PcG proteins, in a low expression state, and had no DNA methylation. When the gene received signals for cells to mature, the PcG loops were disrupted and the gene was highly expressed. However, when the same gene was abnormally DNA methylated, as is the case in adult, mature colon cancer cells, the PcG packaging loops were tighter and there was no gene expression. “These tight loops touch and interact with many gene sites folding it into a structure that shuts off tumor suppressor genes,” says Baylin. However, when the researchers removed DNA methylation from the cancer cells, the loops loosened somewhat, back to the state of an embryonic cell, and some gene expression was restored.
DNA methylation is a normal cellular process, but when it goes awry and genes are improperly methylated, it can shut down important tumor suppressing cell functions.
Demethylating agents, drugs that target and remove abnormal DNA methylation from genes, have been introduced as potential new cancer therapies. For these therapies to be fully effective, Baylin says, researchers may also need to look for agents that disrupt PcG loops.
While examining patterns of DNA modification in lung cancer, a team of international researchers has discovered what they say is a surprising new mechanism. They say that “silencing” of a single gene in lung cancer led to a general impairment in genome-wide changes in cells, contributing to cancer development and progression. In the January 1,
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Cancer and cell biology experts at the University of Cincinnati (UC) have identified a new tumor suppressor that may help scientists develop more targeted drug therapies to combat lung cancer. The study, led by Jorge Moscat, PhD, appears in the January 2009 issue of Molecular and Cellular Biology . Proto-oncogenes are genes that play a
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Researchers at Georgetown University Medical Center have found a gene they say is inactivated in two aggressive cancers - malignant melanoma, a form of skin cancer, and glioblastoma multiforme, a lethal brain tumor. They add that because this gene, known as PTPRD, has recently been found to be inactivated in several other cancers as well,
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Canadian researchers are trying to answer why some smokers develop lung cancer while others remain disease free, despite similar lifestyle changes. Results were presented at the American Association for Cancer Research’s Seventh Annual International Conference on Frontiers in Cancer Prevention Research. According to the Centers for Disease Control and Prevention, more people die from lung
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Whitehead Institute researchers have greatly simplified the creation of so-called induced pluripotent stem (iPS) cells, cutting the number of viruses used in the reprogramming process from four to one. Scientists hope that these embryonic stem-cell-like cells could eventually be used to treat such ailments as Parkinson’s disease and diabetes. The earliest reprogramming efforts relied
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