Findings could impact treatment of cancer

BOULDER — Researchers at CU-Boulder have discovered a protein complex linked to tumor growth in the human body that could be targeted with drugs to stunt the spread of cancer.

The studies recently were published in the industry trade journal Cell. The studies show that a particular protein complex in the human body — including its critical enzyme CDK8 — is required by tumor cells to thrive in low-oxygen conditions, according to a press statement from the University of Colorado-Boulder. As tumors grow, their centers are deprived of oxygen.

The studies also show that the enzyme CDK8 works with a protein called hypoxia-inducible factor 1-alpha, also known as HIF1A, which is a master regulator of a cell’s response to low oxygen. HIF1A works through CDK8 to help tumors respond to a low-oxygen environment.

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In general, researchers have struggled to create drugs to stop HIF1A. Now that the CDK8 enzyme has been found to work with HIF1A, it can be targeted by an existing class of cancer treatment drugs known as kinase inhibitors, according to studies.

CU-Boulder researchers made the latest discovery while studying how gene expression is controlled by a protein complex they call Mediator. The research team was led by Joaquin Espinosa, an associate professor of molecular, cellular and developmental biology at CU, and Matthew Galbraith, a postdoctoral researcher in Espinosa’s lab.

“This is a clear example of starting with a basic biology question that now turns out to be relevant to patients,” Espinosa said in the press statement.

Researchers received an undisclosed amount of funding from the National Science Foundation to better understand how the CDK8 enzyme works.

“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.

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.

“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.