In an article posted by the BBC, researchers in the UK
discovered that a gene was being switched off in the cancerous cells of pancreatic
tumors (pancreatic ductal adenocarcinomas). The gene, USP9x,
which normally prevented cells from dividing uncontrollably, was being turned
off by other proteins and chemicals becoming stuck to it (similar to the
analogy we have discussed in class of the brakes being cut off in a car). Interestingly
enough, David Tuveson, a researcher from the Cancer Research UK Cambridge Research
Institute, said “we suspected that the fault wasn’t in the genetic code at all,
but in the chemical tags on the surface of the DNA that switch genes on and off,
and by running more lab tests we were able to confirm this.”
In examining the official study published in the journal, Nature, it seems researchers used a
mouse model of pancreatic ductal preneoplasia. According to the researchers,
the “most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50%
of the tumors.” They stated that loss of Usp9x protects cancer cells from anoikis (a type of programmed cell
death). The loss of Usp9x, a tumor
suppressor gene, in conjunction with the oncogene, KrasG12D, accelerated pancreatic tumorigenesis in mice. Researchers also speculated that the
loss of Usp9x disabled the ITCH
function (the ITCH gene is involved in the transportation of proteins in a
cell); the Usp9x-ITCH pathway “may
work to constrain pancreatic tumorigenesis.” The researchers went on to say that
further study of the Usp9x-ITCH
pathway was “warranted.”
The “chemical tags” on the surface of DNA that the author of
the article in the BBC describes most likely relates to promoter regions in the
Usp9x gene. Researchers treated human
cell lines with DNA methylase inhibitor and saw a moderate increase in the
production of Usp9x mRNA and
proteins, which indicated that the gene could be epigenetically silenced in vivo (normally methylation represses
transcription of a certain region of DNA leading to “gene silencing”). Essentially,
this illustrated one potential mechanism in the regulation of Usp9x in pancreatic ductal
adenocarcinomas.
The researchers in the study also briefly mentioned how Usp9x was recently involved in another
study, which indicated that the gene served as “pro-survival gene” (somewhat
conflicting with their work). The researchers cautioned that Usp9x-inhibitor drugs perhaps may not be
helpful or useful for patients. It is interesting to note how science can sometimes
conflict, and it really it shows how much we have yet to learn about the
complicated biological processes that occur in our body. It also shows how one experiment might
yield different results for different reasons, which might indicate an
error in one experiment or a discovery of something previously unobserved. It
also highlights the importance of communication in the field of science:
hopefully scientists can come together and figure out exactly what role Usp9x plays in the body.
In the conclusion of the report, the researchers in the
study said that the reason why previous DNA sequencing efforts had not
identified Usp9x as a participant in
carcinogenesis is a result of the fact that the gene is silenced in pancreatic
ductal adenocarcinoma. Which leads me to question of how many other silenced
genes are out there contributing to cancer tumorigenesis?
References:
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11114.html
http://www.bbc.co.uk/news/health-17870315
References:
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11114.html
http://www.bbc.co.uk/news/health-17870315