The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC–WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt’s lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC–WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC–WDR5 inhibitors could be developed as anticancer agents.
Lance R. Thomas,a Clare M. Adams,b Jing Wang,c April M. Weissmiller,a Joy Creighton,a Shelly L. Lorey,a Qi Liu,d Stephen W. Fesik,e Christine M. Eischen,b and William P. Tanseya,1
For reagents we thank C. Bautista, C. Cepko, and F. Zhang. The VU Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). The Thomas Jefferson Flow Cytometry and Research Animals shared resource cores are supported by the Sidney Kimmel Cancer Center National Cancer Institute (NCI) P30CA056036 grant. VANTAGE is supported by the Vanderbilt Ingram Cancer Center, the Vanderbilt Vision Center (P30EY08126), and NIH/National Center for Research Resources (G20RR030956). This project has been funded in part with federal funds from the NCI, under Chemical Biology Consortium Contract No. HHSN261200800001E. This work was also supported by grants from the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (to W.P.T. and S.W.F.), the TJ Martell Foundation (to W.P.T. and S.W.F.), St. Baldrick’s Foundation (W.P.T.), Alex’s Lemonade Stand Foundation (W.P.T.), Edward P. Evans Foundation (W.P.T.), the NCI/NIH (CA200709; W.P.T.), the NCI/NIH (CA211305; L.R.T.), the NCI/NIH (CA148950; C.M.E.), the Integrated Biological Systems Training in Oncology Training Program (T32 CA119925; A.M.W. and W.P.T.), the Rally Foundation for Childhood Cancer Research Fellowship (A.M.W.), Open Hands Overflowing Hearts cofunded research fellowship (A.M.W.), the American Association for Cancer Research Basic Cancer Research Fellowship (A.M.W.), and the Sidney Kimmel Cancer Center/Thomas Jefferson University.
Proceedings of the National Academy of Sciences of the U S A. 2019 Dec 10; 116(50): 25260–25268. Published online 2019 Nov 25. doi: 10.1073/pnas.1910391116; PMCID: PMC6911241; PMID: 31767764; PNAS Plus; Medical Sciences
For full online article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911241/