Using an approach that combines molecular biology, genetics, cell biology and physiology, and pathology, researchers at the University of Pittsburgh Cancer Institute (UPCI) and the University of Pittsburgh School of Medicine have identified a protein that governs a key molecule involved in orchestrating the balance between tumor growth and tumor suppression. The findings, published today in Molecular Cell, reveal a regulatory pathway that could provide new targets for future cancer treatment.
Kruppel-like factor 4 (KLF4) is one of four molecules known to play an important role in transforming the body’s mature cells back into stem cells, said senior author Yong Wan, Ph.D., associate professor, Department of Cell Biology, Pitt School of Medicine and UPCI. His team began studying KLF4 to better understand its biology.
“This molecule has been shown in other studies to encourage tumor growth in some cases, such as breast cancer, but to suppress it in others, such as gastrointestinal cancer,” he said. “We wanted to learn how that was possible.”
From a cultured cancer-cell line, the researchers began purifying proteins and examining their interactions using sophisticated combinatorial techniques. They found that a protein made by the von Hippel-Lindau gene (pVHL) binds to KLF4 and triggers a biochemical pathway that leads to KLF4’sdegradation.
Dr. Wan noted that KLF4 determines cell fate by activating or inhibiting a network of genes involved in cellular functions as diverse as cell cycle regulation and metabolism, stem cell renewal and cell death. In some cells, it leads to production of proteins that suppress cell proliferation. That means pVHL performs a balancing act: if it is high, the lifespan of KLF4 shortens; if it is low, KLF4 lasts longer, with a consequent impact on the number of cells.
“In colon cancer cells, pVHL levels are high and KLF4 is low, which suggest promotion of tumor cell growth,” he said. “But our other research shows that in breast cancer, KLF4 is high. The abnormal proteins produced by cancer cells could be influencing this pathway, so we are working to better understand these processes.”
Learning more about the role of pVHL, KLF4 and other proteins that interact with them could also lead to new cancer drugs, the researchers said.
Co-authors of the paper include Armin M. Gamper, Ph.D., Xinxian Qiao and Liyong Zhang, Ph.D., of the Department of Cell Biology, Pitt School of Medicine, and UPCI; Jennifer Kim of Carnegie Mellon University; and Michelle C. DeSimone and W. Kimryn Rathmell, M. D., Ph.D., of the University of North Carolina. The research was funded by National Institutes of Health grants CA154695 and CA115943 and the American Cancer Society.