Possible 'Central Hub' Proteins Found in Cancer Cell Growth

A study from researchers at The Children’s Hospital of Philadelphia may add new lines to the textbook description of how cancer cells divide uncontrollably and develop into tumors. Their study, published in Nature Communications, identifies and describes an epigenetic mechanism in cancer cells that amplifies the expression of many genes and could be a central hub in cancer cell growth. Unlike most molecular cancer discoveries that advance knowledge of the disease by dividing it into narrower subtypes, this finding could directly apply to multiple cancer types.

“We know the signaling pathway known as the Rb pathway is altered in pretty much every single tumor that you can find in clinical settings,” said Patrick Viatour, PharmD, PhD, the study’s senior author, an investigator at CHOP and assistant professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Viatour’s research focuses on a family of proteins in the Rb pathway, called E2f transcription factors, that are an important part of the process of cell division — the cell cycle of reproduction that is carefully controlled in healthy cells but proceeds out of control when cancer cells proliferate. Transcription factors, including the E2f family of proteins, bind to specific target regions of DNA and help to either activate or deactivate expression of certain genes.

As a result of Rb pathway alteration, E2f factors are steadily turned on in cancer. In the study primarily using a mouse model of liver cancer, Dr. Viatour and his team found that E2f1 progressively accumulates as cancer progresses.

“E2f1, an activating E2f transcription factor, is frequently overexpressed in late stages of many types of cancer, both pediatric and adult,” Dr. Viatour said. “We know it’s linked to late cancer stages and poor prognoses, but we didn’t know what it was doing.”

The scientists showed how E2f1 enables excessive gene activation in the cancerous cell: As E2f1 accumulates, it amplifies gene activation by other members of the E2f family by binding to a molecular complex of the DNA-unzipping proteins Pontin and Reptin. When bound to this complex, the adjacent chromatin molecules that store and protect DNA open up and allow all of the other activating E2f proteins to enter and bind to their target sites.

They found that when excess E2f1 forms the Pontin/Reptin complex on DNA in cancer cells, not only do cell-cycle genes become overactivated, but many more genes are also overexpressed. This occurs because, in the presence of amplified E2f factors, more of these factors will bind to genes that possess lower affinity for them.

In particular, some of these other genes regulate a long-known process of rewiring the energy metabolism in cancer cells for rapid growth, known as the Warburg effect. Dr. Viatour and colleagues believe many more genes are activated by this amplification mechanism, as well. They suggest that the mechanism connects excess cell proliferation together with other characteristic features of cancer cells that collectively make up the process of tumor formation.

“This finding really expands what’s been considered textbook material,” Dr. Viatour said. “We thought E2f was mostly promoting cancer growth through aberrant cell cycle activity. If you only have a little E2f activity, it is just the cell cycle. But if you have a lot of E2f activity, as you have in cancer, it’s way more than that. These factors promote cancer progression by actually activating multiple gene programs.”

Although most of this work was done in a mouse model of hepatocellular carcinoma, a form of liver cancer primarily affecting adults, Dr. Viatour and his team performed further experiments using human cell lines from multiple types of pediatric and adult cancers. In just over half of these human cell experiments, they found the same Pontin/Reptin complex binding with E2f1, suggesting that the same mechanism may occur in many human cancers.

The team’s next phase of research will seek to better understand this mechanism of amplified gene expression to determine whether it is not only associated with cancer progression, but truly critical to it. If so, Dr. Viatour said, there is potential to pursue cancer treatments that would target the E2f1/Pontin/Reptin complex in cancer cells to stop excessive gene expression before it starts. Transcription factors such as E2f1 itself are so ubiquitous and essential in healthy cells that they do not make good targets for disease treatments, he noted, but targeting protein-protein interactions has been successful in other cancer therapies.

“I think we have a mechanism that is very general,” Dr. Viatour said. “Maybe we’re wrong, but maybe we’ve hit something that is going to be very relevant to a lot of cancer types. Testing that hypothesis is very exciting.”