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 that an
absolute key to fighting cancer is figuring 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," said Hengmi Cui, assistant
professor of molecular
medicine at Johns
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," Cui said.
Andrew Feinberg, professor of medicine, oncology and
molecular biology and genetics and
director of the Epigenetics Center at Johns 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 said, "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," Feinberg said. "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.
David Gius, of the National Cancer Institute's
Radiation Oncology branch, said, "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."
The research was funded by the National Institutes of
Health.
Authors on the paper are Wenqiang Yu, Patrick Onyango,
Judith Karp, Feinberg and Cui, all of
Johns Hopkins; and David Gius and Kristi Muldoon-Jacobs,
both of the National Cancer Institute.