Protein linked with tumor growth could be potential target for cancer-fighting drugs, according to study led by CU-Boulder

June 6, 2013 •

A team of researchers led by the University of Colorado Boulder has discovered a protein complex that could be targeted with drugs to stunt tumor growth.

As tumors expand, their centers are deprived of oxygen, and so tumors must flip specific genetic switches to survive in these hypoxic environments.

A series of studies published today in the journal Cell reports the discovery of a protein complex that tumor cells require to flip “on” genes that allow them to thrive in low-oxygen conditions. Importantly, a critical part of the protein complex, an enzyme known as CDK8, can be targeted by an existing class of drugs.

The research team — including Joaquín Espinosa, an associate professor of molecular, cellular and developmental biology, and Matthew Galbraith, a postdoctoral researcher in Espinosa’s lab — stumbled upon the discovery while studying how gene expression is controlled by a protein complex called Mediator.

“This is a clear example of starting with a basic biology question that now turns out to be relevant to patients,” said Espinosa, who also is an investigator at the University of Colorado Cancer Center.

The researchers, with funding from the National Science Foundation, were trying to better understand the function of CDK8 in the Mediator protein complex.

“This is an ancient protein complex,” Espinosa said. “But the mechanism of action of Mediator is not well understood.”

For the study, Espinosa, Galbraith and their colleagues depleted CDK8 in cancer cells and then grew the cells with and without stressors, such as low glucose, DNA damage and low oxygen. Without CDK8, cells in hypoxic conditions failed to activate the gene expression program that could help them survive without oxygen.

“Lo and behold, it turns out CDK8 has a major role in controlling gene expression in conditions of low oxygen. A few hundred genes go up to allow the cell to adapt to these conditions, but not without CDK8,” Espinosa said.

In itself, this is a fairly major finding in basic biology, Espinosa said. But it was Espinosa’s connection with the cancer research community that allowed the next step.

“See, we’ve known that the transcription factor HIF1A is a master regulator of a cell’s response to hypoxia. It turns survival genes up when oxygen goes down,” Espinosa said. “HIF1A has been known as a major factor in tumor development, but as a transcription factor it’s notoriously hard to drug.”

The group wondered if CDK8 and HIF1A might work together to regulate the genetic response to hypoxic conditions. It turns out that HIF1A necessarily works through CDK8 to help tumors respond to the hypoxic environment. And while researchers have struggled to create drugs that can inhibit HIF1A from doing its job, the class of drugs known as kinase inhibitors is designed to specifically target enzymes similar in function to CDK8.

“From the start, it was a very mechanistic question: How do cells use the Mediator complexes to turn genes on and off? Now we find this same system is important for tumor hypoxia,” Espinosa said. “We entered from the CDK8 angle, landed right on the known oncogene HIF1A, and are back to CDK8, now with very real clinical potential.”

Contact:
Joaquín Espinosa, 720-938-2556
Joaquin.Espinosa@colorado.edu
Laura Snider, CU media relations, 303-735-0528
Laura.Snider@colorado.edu

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