Targeted Treatment of Enzyme Shows Promise in Colorectal Cancer

A study published in Cell Reports discovered the role the enzyme TIP60 plays in colorectal cancer and the ability of cells to survive in low oxygen.

“Tumors often can't grow the new blood vessels needed to supply themselves with the oxygen that most tissues would need to grow,” said researcher Matthew Galbraith, PhD. “In order to survive in low oxygen — in conditions of hypoxia – tumors produce the protein HIF1A. In human tumors, hypoxia and high expression of HIF1A are both predictors of bad outcomes.”

It has previously been proven extremely difficult to inhibit HIF1A, so many researchers have conducted studies to identify cofactors of HIF1A to overcome this hurdle. Two labs in Buenos Aires took different approaches to identify HIF1A cofactors.

Joaquín Espinosa, PhD, and Galbraith used human cancer cells grown in petri dishes, while Joel Perrez-Perri and Pablo Wappner used fruit flies.

In the Espinosa lab, researchers were able to identify the enzyme CDK8, which is required for most of HIF1A activity in cancer cells. In the Wappner lab, researchers identified TIP60, which is required for HIF1A activity in flies.

In the current study, Galbraith and Espinosa teamed up to determine if the role of TIP60 in the response to hypoxia in flies was also conserved in human cancer cells.

“It was a nice coincidence and a great opportunity to collaborate with fellow scientists in Argentina, the country where I was born, raised and received my education,” Espinosa said. “I invited Joel to come to our lab in Colorado to spend a few months learning how to work with human cancer cells.”

The results of their combined study efforts showed that the role of TIP60 is conserved in human colorectal cancer cells. These cells require CDK8, TIP60, and HIF1A to form small tumors in the lab.

“By depleting CDK8 and TIP60 in colorectal cancer cells, we shut down more than 60% of the cellular activity of HIF1A, and this suffices to block their tumor-initiating ability,” Galbraith said.

Researchers sought to determine whether the molecular mechanisms of TIP60 promoted HIF1A activity. Graduate student Veronica Dengler found that HIF1A and TIP60 work together in order to turn on numerous genes in the cell nucleus, including the key genes needed for the cellular adaptation to hypoxia.

“This study absolutely demonstrates the importance of basic research,” Galbraith said. “Here we had something in a fruit fly that didn't have any obvious connection to cancer and it turns out to be an important player in one of the most critical networks of cancer survival signaling.”

Researchers hope that the findings will jumpstart interest in examining the function and potential inhibition of CDK8 and TIP60 in cancer.

“What I love about this project is that it illustrates the power of collaboration and training efforts,” Espinosa said. “In order to make these important discoveries, we assembled a team of scientists from Buenos Aires, Colorado and Wisconsin, in academia and industry, to work with 2 graduate students located 6000 miles apart.”