An enzyme that fights off viruses may also accelerate cancer evolution

A study led by researchers at Weill Cornell Medical College has shown that an enzyme that protects human cells from viruses can help propel cancer toward more serious malignancy by causing countless mutations in cancer cells
.
This finding suggests that this enzyme could be a potential target for
future cancer treatments.

In the new study, published Dec.
8 in Cancer Research, scientists used a preclinical model of bladder cancer to study the role of an enzyme called APOBEC3G in promoting disease progression and found that it significantly increased the number of mutations in tumor cells, increased the genetic diversity of bladder cancer, and accelerated mortality
.

"Our findings suggest that APOBEC3G is an important factor in the evolution of bladder cancer and should be considered a target for future therapeutic strategies," said Bishoy M.
Faltas, Ph.
D.
, senior author of the study, assistant professor of cell and developmental biology at Weill Cornell Medicine and an oncologist
at New York-Presbyterian/Weill Cornell Medical Center specializing in urothelial cancer.

The APOBEC3 family of enzymes is able to mutate RNA or DNA
by chemically modifying cytosine nucleotides (the letter "C" in the genetic code).
This can lead to the production of erroneous nucleotides
at that location.
The normal role of these enzymes, including APOBEC3G, is to fight retroviruses like HIV — which try to impede the replication of viruses by mutating cytosines in the viral genome
.

The inherent dangers of these enzymes suggest that there must be some mechanism to prevent them from harming cellular DNA
.
However, starting about a decade ago, researchers using new DNA sequencing techniques began to find widespread APOBEC3G-type mutations
in cellular DNA in the context of cancer.
In a 2016 study of human bladder tumor samples, Dr.
Faltas, who is also director of bladder cancer research at the Institute for Precision Medicine England and a member of the Sandra and Edward Mayer Cancer Centre, found that a large proportion of mutations in these tumors were associated with APOBEC3G, and that these mutations appeared to play a role
in helping tumors evade the effects of chemotherapy.

These findings point to the possibility
that cancers often use APOBEC3s to mutate their genomes.
This not only helps them acquire all the mutations they need for cancer to grow, but also enhances their ability to diversify and "evolve" — allowing them to grow and spread
further in the face of immune defenses, drug treatments, and other adverse factors.

In the new study, Dr.
Faltas and his team, including first author Weisi Liu, PhD, postdoctoral research assistant, addressed the specific role
of APOBEC3G in bladder cancer through direct causal experiments.

APOBEC3G is a human enzyme that mice do not have, so the team knocked out the only APOBEC3G enzyme gene in mice and replaced it with a gene for human APOBEC3G
.
The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimicked a carcinogen in cigarette smoke, they were more likely to develop this form of cancer (76 percent developed cancer), compared to mice whose APOBEC3G gene was knocked out and not replaced (53 percent developed cancer
).
In addition, all of the knockout mice survived during the 30-week observation period, while nearly one-third of the APOBEC3G mice died of cancer
.

To their surprise, the researchers found that APOBEC3G in mouse cells was present in the nucleus, which used "light sectioning" microscopy techniques to preserve cellular DNA
.
Previously, this protein was thought to exist only outside
the nucleus.
They also found that APOBEC3G mice had twice as many bladder tumors as tumors in pure knockout mice
.

By identifying specific mutational signatures of APOBEC3G and mapping them into the tumor genome, the team found ample evidence that the enzyme creates greater mutational burden and genomic diversity in tumors, which may be responsible for
higher malignancy and mortality in APOBEC3G mice.
"We found clear mutational features caused by APOBEC3G in these tumors, which are different
from those caused by other members of the APOBEC3 family," said Dr.
Liu.

Finally, the researchers looked for mutation signatures for APOBEC3G in the Cancer Genome Atlas, a widely used database of human tumor DNA, and found that these mutations appeared to be common in bladder cancer and were associated with
worse outcomes.

"These findings will inform
future efforts to limit or guide tumor evolution by targeting the APOBEC3 enzyme with drugs," said Dr.
Faltas.