By Suneethi Sivakumaran
The human body is a complicated network of interdependent cellular processes regulated by gene-encoded proteins. Proteins maintain these processes by exerting diverse functions in different cells. Although the function of many proteins is consistent between cell types, sometimes, one protein will “moonlight” by carrying out different physiological functions in different cells.
WDR5, a small and highly-conserved protein, and has moonlighting roles in chromatin regulation and in chromatin-independent processes such as cell division. It also serves as a cofactor for proteins such as retinoic acid receptor and MYC. WDR5 exerts these diverse functions through either of its two binding sites, a WDR5-binding motif, WBM, and a WDR5-interacting site, WIN.
WDR5 is overexpressed in multiple cancer types, and its oncogenic role makes it a promising target for anti-cancer therapies; new drugs often target the WBM and WIN binding sites. Prior research from the lab of Bill Tansey, professor of cell and developmental biology and biochemistry, led to the discovery of small molecule inhibitors of the WIN site and the characterization of their mechanism of action, but considering the diverse moonlighting roles of WDR5, the lab wanted to determine which, if any, of the protein’s roles are central to its function. Their most recent results were published in Nucleic Acids Research.
The Tansey group originally reported that WDR5 bound to chromatin at genes involved in protein synthesis, a process that is frequently deregulated in cancer, in a leukemic cell line. They also showed that the WIN inhibitors displaced WDR5-bound chromatin from these sites and activated apoptosis, or programmed cell death, in those cells.
To determine if WDR5’s WIN site regulates the same network of protein synthesis genes in all cancer cells or just in leukemia cells, and to test whether the WIN site inhibitors have similar anti-cancer effects in other cell types, the researchers studied WIN site-mediated gene regulation in several mouse and human cell types. By using one of the WIN inhibitors they developed in their previous paper and by conducting comparative genomic analyses, the Tansey lab found that, through its WIN site, WDR5 binds to and regulates protein synthesis genes across all cancer cells.
Thanks to the diverse roles WDR5 performs, the mechanism of action of WIN site inhibitors lacked clarity. This study sheds light on the conserved role of the WIN site in regulating a gene network involved in protein synthesis across human and mouse cancer cells, paving the way for the use of WIN site inhibitors as broad anti-cancer agents in the clinic.
This research was supported by the National Institutes of Health, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, the TJ Martell Foundation, Edward P. Evans Foundation, the Rally Foundation for Childhood Cancer Research, Open Hands Overflowing Hearts, and the American Association for Cancer Research.