Sci. Aging Knowl. Environ., 29 January 2003
Down But Not Out
Stripping chemical ornaments can reactivate cancer-thwarting gene
Key Words: methyltransferase epigenetic CpG
A simple chemical alteration can resuscitate a protein that protects cells from cancer, according to new research. The results reveal that modifying certain DNA-binding proteins can inactivate genes without the need for changes to the DNA, as previously thought. In addition, the work suggests a way to slow tumor growth without replacing broken genes.
Genes shut down when DNA winds tightly around proteins called histones and switch on when DNA loosens. Chemical adornments on the DNA and particular histones adjust the degree of DNA constriction. When methyl groups embellish the gene's DNA and histone H3, genes hush up. Researchers thought that cancer cells turn off genes that foil tumor formation by methylating first the DNA and then histone H3. However, when cells in women shut down one of their two X chromosomes, histone methylation precedes DNA decoration, suggesting that histones set silencing in motion. To better understand how cells become malignant, Bachman and colleagues wanted to determine the order of events in colon cancer cells. They studied the tumor-suppressor gene p16, which normally restrains growth but is disabled in some cancers.
In earlier work on colon cancer cells, Bachman's team found that deleting two genes that methylate DNA revives production of p16 and halts uncontrolled growth. The cells, however, eventually regain their cancerlike fecundity. The researchers wanted to know whether cells reverted to cancerous growth by turning p16 off again, or whether they inactivated another tumor-suppressor gene. They found that cells lacking p16 as well as the methylators divided briskly, indicating that unrestricted growth--and hence the cancer relapse--is caused by the loss of operational p16.
To figure out how the absence of methylators awakens p16, the researchers examined structural changes to the gene and its associated histones in cells engineered to lack the two DNA-methylation genes. They suspected that restoring methylation to either DNA or histones might sedate p16, so they compared slow- and fast-growing cells. In sluggish cells, histone H3 lacked its methyl group, and the amount of methylation on the p16 gene was one-tenth that in cancer cells. But in speedy cells, the DNA lacked chemical accessories, whereas histone H3 had acquired its adornments. What's more, the researchers could not detect p16 in these cells. Because histone methylation occurred at the same time that p16 quieted down--and while the gene's DNA remained unmethylated--the results suggest that cancer cells need only methylate histone H3, not DNA, to turn off the gene that halts growth.
"The work is exciting from a therapeutic standpoint, because the tumor-suppressor gene is reactivateable," says biochemist C. David Allis of the University of Virginia, Charlottesville. Researchers might stop cancer by turning the suppressor gene back on, using drugs that inhibit histone methylation instead of genetically manipulating cells. Furthermore, says Allis, cells can control p16 protein production by packing the DNA with marked histone H3: "[The researchers have] found this whole other layer of regulation." Perhaps that finding will help them take control of the switch that turns on cancer.
K. E. Bachman, B. H. Park, I. Rhee, H. Rajagopalan, J. G. Herman, S. B. Baylin, K. W. Kinzler, B. Vogelstein, Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89-95 (2003). [Abstract] [Full Text]
January 29, 2003 Citation: M. Beckman, Down But Not Out. Science's SAGE KE (29 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/4/nw17
Science of Aging Knowledge Environment. ISSN 1539-6150