Scientists take 'RESTful' approach to understanding cancer

By Ruth SoRelle, M.P.H.

Proteins called tumor suppressors play important roles in preventing cancer. However, when something happens to inactivate them, the results can be devastating.

Understanding what prevents these proteins from suppressing tumor activity can help scientists and, ultimately, physicians stop cancer in its tracks. In a recent study in the journal Nature, Baylor College of Medicine scientists explain how an enzyme marks a critical protein called REST for degradation in the cell.

The protein REST (RE1-silencing transcription factor) normally prevents ordinary body cells from being like nerve cells or neurons. It is also a tumor suppressor gene – preventing common epithelial cells from becoming cancers.

Tumor supressing function

"Epithelial cancers from the breast and lung frequently over-express neuronal genes, and the discovery that REST is a tumor suppressor in these tissues helps to explain this," said Thomas Westbrook, Ph.D., assistant professor of biochemistry and molecular biology at BCM and first author of the report. The research represented in the report was done while he was a postdoctoral associate in the laboratory of Stephen J. Elledge, professor of genetics at Harvard Medical School and a former BCM faculty member.

To understand how REST is inactivated in cancer, Westbrook used a technique called RNA interference (RNAi) to find genes that reduce REST levels. Westbrook predicted that this approach would find oncogenes, which promote cancer.

Sinister function

Westbrook and his colleagues identified a protein called TRCP that degrades REST, allowing its elimination from the cell at critical points of nervous system development.

But TRCP also has a more sinister function.

"When TRCP helps eliminate REST in the wrong cell types, it promotes breast cancer," said Westbrook.

Eliminating cancer

Understanding how TRCP disables REST could help provide a new way to kill cancer cells. TRCP was already known to initiate breast cancer. In experiments, however, Westbrook and his colleagues found that by reconstituting REST in the cell, they eliminated the cancer-causing function of TRCP.

Intriguingly, REST must be primed with a phosphate molecule for it to be degraded by TRCP, suggesting that enzymes that add phosphates to REST may also be involved in cancer.

"This discovery gives us a new window into finding the enzymes called kinases and phosphatases that control tumor development," said Westbrook. "This is particularly exciting, because the scientific community is good at inhibiting this class of enzymes with therapeutic drugs."

Stem cell implications

Right now, the three cancers most likely to be approachable by this method are breast, colon and small cell lung cancers.

This discovery also has implications for stem cell biology. REST becomes unstable early in the differentiation process of nerve stem cells.

"By understanding how REST is degraded during stem cell differentiation, we may offer new strategies to cause stem cells to produce new neurons in people challenged with neurodegenerative diseases," said Westbrook.

Others who took part in this work include Guang Hu, Xiaolu L. Ang, Peter Mulligan, Natalya N. Pavlova, Anthony Liang, Yumei Leng, Rene Maehr, Yang Shi and J. Wade Harper, all of Harvard.

Funding for this work comes from the Susan G. Komen Foundation, the Helen Hay Whitney Foundation, the National Institutes of Health, the U.S. Army and the Howard Hughes Medical Institute.

The report can be found at www.nature.com.