Jefferson Scientists Uncover Role of Cancer Stem Cell Marker: Controlling Gene Expression Patterns
Scientists
at Jefferson’s Kimmel Cancer Center in Philadelphia have made an
extraordinary advance in the understanding of the function of a gene
previously shown to be part of an 11-gene “signature” that can predict
which tumors will be aggressive and likely to spread. The gene, USP22,
encodes an enzyme that appears to be crucial for controlling large
scale changes in gene expression, one of the hallmarks of cancer cells.
As
a result, USP22 immediately becomes a potential target for new
anti-cancer drugs, says Steven McMahon, Ph.D., associate professor of
Cancer Biology at Jefferson Medical College of Thomas Jefferson
University, who led the work. And it solves a bit of a biological
mystery.
Researchers
knew that the gene USP22 was part of a group of 11 genes that are
overexpressed in a variety of cancers and that overexpression of USP22
predicts which tumors can go on to spread elsewhere in the body. This
group of genes is collectively called the “cancer stem cell signature.”
“Such
cancers that have those properties – going on to be metastatic and
resistant to therapy – are referred to as having cancer stem cell-like
features,” Dr. McMahon explains. “The genes in the signature are in a
family of genes implicated as cancer stem cell markers. Many of them
code for critical components of signaling pathways that are altered in
cancer, making proteins that play roles in tumor growth.” But unlike
the other genes in the stem cell signature, the exact function of USP22
was not known.
Reporting January 18, 2008 in the journal Molecular Cell, Dr. McMahon and his co-workers have shown that not only is USP22 overexpressed in cancer cells, its enzymatic activity is
necessary for some of the global changes in gene expression patterns that occur in these cells.
In
one example, they looked at the relationship between MYC and USP22.
MYC, which is among the most commonly overexpressed genes in cancer,
encodes a protein that controls the expression of thousands of other
genes. The scientists showed that USP22 is a critical partner of MYC
and that by depleting cells of USP22, they could prevent MYC from
working properly, stopping it from inducing the invasive growth of
cancer cells.
“We’ve
shown that the MYC pathway is among the transcriptional programs that
require USP22,” Dr. McMahon says. “Identifying USP22 as a global
transcription regulator helps explain why it is part of this aggressive
stem cell signature.”
Dr.
McMahon and his group determined how USP22 works at the biochemical
level and found that it is part of a large complex of proteins called
human SAGA. According to Dr. McMahon, these proteins are responsible
for turning on genes, helping them get expressed more efficiently. This
suggests that the genes that are turned on by the USP22 complex are
important for altering cancerous cells in such ways that they become
more aggressive and metastatic.
“Discovering
the identity of the 11-gene signature that predicts aggressive,
therapy- resistant tumors a few years ago was certainly a critical
advance in terms of the ability to diagnose and stratify patients,” Dr.
McMahon says. “Since USP22 is an enzyme, the type of protein that is
easiest to target with drugs, our new findings may help extend these
earlier discoveries to the point where therapeutics can be developed.
There are already drugs being used in cancer patients that attack other
enzymes in this pathway, and there are companies interested in
extending this to find USP22 inhibitors.”
Media Only Contact:
Steve Benowitz
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 1/21/2008