One way cancer arises is when tumor suppressor genes that normally keep cell growth in check are mysteriously turned off.
Now, researchers at Johns Hopkins have discovered that at least one tumor suppressor gene is in fact turned off by a “noncoding” single stranded RNA nucleic acid similar to its double-stranded DNA cousin.
The so-called antisense RNA is made by a gene on a neighboring strand of DNA. Most genes in the human genome have associated with them nearby antisense RNAs, which, as their name implies, are complementary to the amino acid sequences in a “sense” RNA to which they may bind and switch off.
Reporting on the discovery in the Jan. 10 issue of Nature, the Johns Hopkins team says an absolute key to fighting cancer is to figure out why and how tumor suppressor genes get silenced and identifying means of switching them back on chemically.
“This is the first time we've seen an antisense RNA silencing a tumor suppressor through the means of epigenetic changes,” says Hengmi Cui, Ph.D., assistant professor of molecular medicine at Hopkins. Epigenetic changes refer to heritable changes in genetic material that are not changes in the sequence of the DNA; these could include the addition of chemical tags onto DNA or otherwise altering how compressed the DNA is in a cell.
The Johns Hopkins team notes that a similar phenomenon occurs in plants but until now has not been seen in any type of animal, including humans. “We're really excited to see if this is a general mechanism for all tumor suppressor genes,” says Cui.
Andrew Feinberg, M.D., M.P.H., professor of medicine, oncology and molecular biology and genetics and director of the Epigenetics Center at Hopkins, says the results of the team's experiments “bring us closer to solving two outstanding mysteries in biology, namely what all those noncoding RNAs do in cells and how tumor suppressor genes get turned off.” It turns out, he adds “that many of those noncoding RNAs may be silencing tumor suppressor genes.”
Following clues that suggested such a role for antisense RNA, the researchers first surveyed computer databases for tumor suppressor genes with known neighboring antisense RNAs. They found antisense counterparts to 21 well-known tumor suppressor genes and decided to further study one of them, p15. That gene is deleted or silenced in several types of human cancer, including melanomas, gliomas, lung and bladder carcinomas and up to 60 percent of leukemias.
The research team first analyzed leukemia cells for the presence of antisense p15. Of 16 patient samples, 11 showed an increase in antisense p15 and decreased p15. The researchers confirmed in other experiments that the more antisense p15 a cell contained the less sense p15 it was likely to have, strong evidence that the antisense was somehow turning down the normal, sense version.
Chemically turning on the antisense gene, the team found, turned off the sense p15 gene. When they looked at the DNA around the p15 gene in cells, they found that the DNA was more compact and tightly packaged, which generally shuts off genes.
“Somehow, the presence of the antisense RNA leads to the formation of this tightening of the chromosome to make heterochromatin around the p15 gene, turning it off,” says Feinberg. “We're now looking at other tumor suppressor genes to figure out how this happens and how general this phenomenon is.”
Further characterization of the antisense RNAs, according to Feinberg, could lead to their use as markers for certain types of cancer as well as targets for cancer-specific drugs and therapies.
“This initial laboratory study gives us some excellent clues of how to proceed with possible clinical studies to determine whether antisense RNAs could be used to guide therapy,” says David Gius, M.D., Ph.D., of the National Cancer Institute's Radiation Oncology branch.