In ovarian cancer, researchers uncover new drivers of cell division

In a study published in the journal Molecular and Cellular Biology, UNC Lineberger researchers report that they’ve discovered a key activator that can turn on FoxM1, a protein that drives expression of genes that help cells replicate and divide. They also discovered, paradoxically, that the activator for FoxM1 is also responsible for turning this protein off.

In ovarian cancer, researchers uncover new drivers of cell division click to enlarge Michael J. Emanuele, PhD, is a UNC Lineberger member and assistant professor in the Department of Pharmacology.
In ovarian cancer, researchers uncover new drivers of cell division click to enlarge Victoria Bae-Jump, MD, PhD, is a UNC Lineberger member and associate professor in the UNC School of Medicine Department of Obstetrics & Gynecology.

Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have identified some of the bad actors that can step on the gas to help drive cells to replicate and divide abnormally in ovarian cancer.

In a study published in the journal Molecular and Cellular Biology, researchers report that they’ve discovered a key activator that can turn on FoxM1, a protein that drives expression of genes that help cells replicate and divide. They also discovered, paradoxically, that the activator for FoxM1 is also responsible for turning this protein off.

The finding could help direct future lines of research that target this FoxM1 activator, which could lead to a possible therapeutic approach for ovarian cancer, the fifth leading cause of cancer death in women in the United States.

“If we can understand what tips the balance of the regulation of this protein, we might have an entry point for therapeutically inactivating FoxM1 by triggering its destruction,” said the study’s corresponding author Michael J. Emanuele, PhD, a UNC Lineberger member and assistant professor in the Department of Pharmacology.

Researchers in Emanuele’s laboratory study how, when and why cells dispose of unneeded proteins. Specifically, they are focused on the ubiquitin system, which can place the “mark of death” on proteins that are no longer needed so that they can be chewed up and destroyed. In many diseases, and particularly in cancer, these disposal mechanisms can become unregulated and drive cell growth, Emanuele said.

Researchers know that FoxM1, which is regulated by the ubiquitin system, is activated in certain cancers. FoxM1 is a type of transcription factor that drives expression of genes that are involved in replication and segregation of our genetic material. Turning on FoxM1 is like putting gas in the tank to fuel cell division, Emanuele said.

“But what’s stepping on the gas?” he said.

In their study, researchers found that a protein called VprBP/DCAF1 can activate FoxM1, and that VprBP is overexpressed in high-grade serous ovarian tumors. Surprisingly, they also found that VprBP is involved in turning off FoxM1 by triggering its degradation.

“It was very, very surprising that the protein that cells are using to get rid of FoxM1 is also important for turning it on,” Emanuele said.

Understanding how FoxM1 is controlled could provide insight into how it can be targeted for therapeutic benefit, Emanuele said. To that end, future studies will explore exactly how VprBP can degrade – and activate -- FoxM1.

And researchers said new therapies are sorely needed for ovarian cancer.

“Few targeted therapies exist for ovarian cancer,” said Victoria Bae-Jump, MD, PhD, a UNC Lineberger member and associate professor in the UNC School of Medicine Department of Obstetrics & Gynecology. “VprBP may be a promising target in ovarian cancer, a disease where novel therapeutics are desperately needed to improve outcomes.

Epithelial ovarian cancer is often asymptomatic in its earliest stages. As a result, many women are diagnosed with advanced cancer that is more difficult to treat successfully, said Bae-Jump. In addition, there is a high rate of recurrence despite aggressive treatment. 

“There is great need for novel targeted therapies for ovarian cancer, which should come with a better understanding of the underlying biology driving the development and progression of this disease,” Bae-Jump said.

In addition to Emanuele and Bae-Jump, other authors include Xianxi Wang and Rjarshi Choudhury of UNC Lineberger; Anthony Arceci of UNC Lineberger and the UNC Curriculum in Genetics and Molecular Biology; Kelly Bird of the UNC Eshelman School of Pharmacy; Christine A. Mills, Jennifer L. Kernan and Albert Bowers of UNC Lineberger and the UNC Eshelman School of Pharmacy; and Chunxiao Zhou of UNC Lineberger and the Division of Gynecologic Oncology.

Researchers were supported by the University Cancer Research Fund, Susan G. Komen, the V Foundation for Cancer Research, and the National Institutes of Health.