Oxford team fingers an inflammatory protein as a trigger for cancer

Oxford's Nick La Thangue

Researchers from Oxford University working on a protein named PAD4 have made new tracks in identifying its role in cancer, spotlighting a new therapeutic strategy for cancer drug hunters.

Nick La Thangue from Oxford University's Oncology Department and his team published their work this month in the journal Science Advances.

Peptidyl arginine deiminase 4, or PAD4, is an enzyme that plays a role in gene expression which in turn controls how functional elements of DNA are utilized. PAD4 plays an important role in inflammatory diseases such as arthritis as well as in cancer development--but just how it functions in a cancer cell is unknown.

"As our understanding of the mechanisms underlying inflammation has increased, interest in PAD enzymes as targets for treatments has grown. PAD4's presence in cancer was well known but its role was not--rather like continually seeing someone at crime scenes but not being able to prove they're involved," said La Thangue.

They discovered that PAD4 could alter the protein E2F-1 by changing one of its amino acids--the building blocks of the protein. The result of this is that E2F-1 can attract another protein called BRD4 which can "read" acetyl groups which can drive the expression of certain inflammatory genes.

E2F-1 is known to play a role in cancer and increases the likelihood of the cancer cells dividing, or proliferating. PAD4 working with BRD4 can help E2F-1 to become more inflammatory than proliferative.

The researchers then tested this approach in special mice bred to develop arthritis by pharmacologically inhibiting PAD4 and BRD4. They observed that lower levels of both proteins ameliorated symptoms of arthritis as well as reduced levels of the associated inflammatory genes.

"Suppressing either of the proteins reduced the symptoms of arthritis but suppressing both saw a marked reduction. Tests also showed that inflammatory products in the body of the mice were reduced. That confirmed the role of both PAD4 and BRD4 is switching E2F-1 to an inflammation role," said La Thangue.

"Inflammation plays a key role in a number of cancers. For example, bowel cancer has an early inflammatory stage. By understanding the biological mechanisms that underlie these cancers, we are better placed to find effective treatments."

- here's the release