By Suneethi Sivakumaran
Cancers are complex and diverse in nature, assailing the human body through different mechanisms. Cancer cells outsmart normal cells through myriad mechanisms, including sustained proliferation, insensitivity to growth suppressors, and resistance to cell death. MYC is a transcription factor (it regulates the expression of other genes) that plays important roles in human development, but it can also favor the growth of cancer cells; MYC is overexpressed in several cancer types, and its inhibition has led to tumor regression, making it an appealing drug target.
Even though drugs that inhibit MYC overexpression or MYC-mediated cellular processes exist, disrupting the binding of MYC to its target genes has been a challenge. A research team led by Bill Tansey (Cell and Developmental Biology) took a different approach: they disrupted MYC’s interaction with a nuclear partner, which then disrupted MYC binding to its target genes. Their approach, which resulted in tumor regression in a Burkitt’s lymphoma mouse model, was published in PNAS.
MYC interacts with MYC-associated factor X (MAX) to regulate gene expression, but recent modeling studies from the Tansey lab showed that ~90% of MYC target gene binding is not mediated by MAX itself, but by other nuclear proteins such as WDR5. That study also showed that structure-guided mutations in MYC disabled its interaction with WDR5, decreased its binding to chromatin and its target genes, and attenuated its tumorigenic potential in mice. Based on these findings, the Tansey team hypothesized that the MYC-WDR5 interaction stabilized MYC-MAX binding and that disruption of the interaction could inhibit the cancer-causing potential of MYC. The team was specifically interested in determining if disruption of the MYC-WDR5 interaction in preexisting tumors could cause tumor regression.
In order to test their hypothesis, they used a Burkitt’s lymphoma cell line and swapped wild-type MYC for a mutant that could not interact with WDR5. The mutant MYC proteins were unable to bind to the chromatin at WDR5-bound sites, genes that are involved in protein synthesis and are often deregulated in cancers, but bound other target genes normally. The team also treated cells expressing wild-type MYC with C6, a small molecule that displaces WDR5 from chromatin, and found that removal of WDR5 from chromatin disrupted MYC binding at sites where WDR5 recruits it; C6 treatment did not disrupt binding of MYC at other target sites, again supporting the idea that the disruption of the MYC-WDR5 interaction affects the binding of MYC at genes targeted by WDR5.
To determine if disruption of the MYC-WDR5 interaction caused tumor regression in vivo, they injected cells expressing either wild-type MYC or the mutant MYC into mice. The mice treated with cells expressing wild-type MYC developed tumors rapidly, while those treated with cells expressing the MYC mutants showed a reduced morbidity and delayed tumor growth, supporting the idea that the MYC-WDR5 interaction was essential for tumor maintenance.
This study demonstrates the significance of the MYC-WDR5 interaction in the regulation of genes involved in protein synthesis and its importance in tumor maintenance, and suggests that MYC-WDR5 inhibitors could be powerful new anticancer drugs.
This research was supported by the National Cancer Institute, the National Institutes of Health, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, the TJ Martell Foundation, St. Baldrick’s Foundation, Alex’s Lemonade Stand Foundation, Edward P. Evans Foundation, the Rally Foundation for Childhood Cancer Research Fellowship, Open Hands Overflowing Hearts cofounded research fellowship, the American Association for Cancer Research Basic Cancer Research Fellowship and the Sidney Kimmel Cancer Center/Thomas Jefferson University.