Important Gene Turned Off in Pancreatic Cancer

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, Kras^G12D, 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