Vanderbilt University researchers have discovered a cleft in a chromosome-binding protein that may hold the key to stopping most cancers in their tracks.
The protein, WDR5, is a “docking station” for a family of transcription factors called MYC that is overexpressed in the majority of malignancies and which contributes to an estimated 100,000 cancer-related deaths each year in the United States.
Once an MYC protein slips a “loop” of itself into the crevice in WDR5, it is able to turn on genes involved in growth and development. In the case of cancer, it turns on runaway growth.
“MYC regulates thousands of genes involved in growth and duplication,” said lead author William Tansey, Ph.D., Ingram Professor of Cancer Research and professor of Cell and Developmental Biology. “It’s sort of the Holy Grail of the targeted cancer therapy world.”
Researchers have tried unsuccessfully to develop small molecules that can bind directly to MYC and block its ignition of cancerous growth. But the discovery of the crevice, reported in this week’s Molecular Cell, opens up a whole new vista of cancer-fighting possibility.
In collaboration with Tansey’s group, a team led by Stephen Fesik, Ph.D., solved the crystal structure of the MYC-WDR5 interaction. Now they’re now testing small molecules for their ability to block the crevice and prevent MYC from binding to the DNA.
Previously it was thought that MYC only needed to attach to another protein called MAX in order to create a DNA-binding “domain” capable of latching onto the DNA. MAX is still in the picture, but it is MYC’s interaction with WDR5 that may be the key to stopping it, Tansey said.
“This (cleft) is a surface you can develop a drug against,” he said. “If someone can make a small molecule that sits in here, then MYC won’t see WDR5 and it won’t get to its chromosomal locations.”
The potential is exciting.
“It’s very clear from preclinical models that inhibiting MYC in just about any cancer will offer some therapeutic opportunity,” Tansey said. If a small molecule is discovered, and is effective in pre-clinical and clinical trials, “you could imagine the impact of this could be quite significant.”
WDR5 has been known to bind chromatin, the DNA-bearing material that makes up chromosomes, for many years.
But its connections to MYC were unknown until Tansey and Lance Thomas, first author of the study, found that a central portion of the MYC protein conserved in nearly every species in the animal kingdom binds to it.
“That’s when we realized this must be important,” he said.
Fesik, the Orrin H. Ingram II Professor of Cancer Research, solved the crystalline structure of the MYC-WDR5 interaction, and disrupted the interaction by changing a single amino acid in the MYC protein.
At that point, three other labs at Vanderbilt joined the effort to determine the functional significance of the interaction:
• Zhongming Zhao, Ph.D., and colleagues in Biomedical Informatics performed the genomics analyses;
• Christine Eischen, Ph.D., and colleagues in Pathology, Microbiology and Immunology developed mouse models to test the tumorigenicity of altered MYC proteins; and
• Kevin Ess, M.D., Ph.D., and colleagues in Pediatric Neurology conducted stem cell experiments to get at the basic biology of the interaction.
“I’ve never been on a paper with this many authors (18 all told),” Tansey said. “I think it really does testify to the fact that (Vanderbilt is) a very collaborative environment.”
The research was supported in part by National Institutes of Health grants AG039164, NS078289, LM011177, CA148950 and OD006933.
