BioProject

The oncoprotein transcription factor MYC is overexpressed in the majority of human cancers. More...

The oncoprotein transcription factor MYC is overexpressed in the majority of human cancers. Key to its oncogenic activity is the ability of MYC to bind chromatin and regulate broad gene expression patterns that drive and maintain the tumorigenic state. The interaction of MYC with chromatin is absolutely dependent on interaction with MAX, but may also be facilitated by additional chromatin-resident proteins such as WDR5. If the role of these additional proteins can be understood, they could serve as novel focal points for therapeutically targeting MYC. To stringently challenge the role of WDR5 in MYC function, we developed a Burkitt's Lymphoma system that allows inducible and quantitative exchange of wild-type for mutant forms of MYC defective for interaction with WDR5 or MAX. Using this system, we show that WDR5 recruits MYC to a small cohort of genes, enriched in those encoding ribosome protein subunits, and demonstrate that disrupting the MYC-WDR5 interaction is as effective as disrupting interaction with MAX at preventing tumor initiation and promoting tumor regression in vivo. These findings show that WDR5 is connected to a central tumorigenic function of MYC and forecast that small molecule WDR5 inhibitors could be broadly effective anti-cancer agents. Overall design: ChIPseq and RNAseq in Ramos cells with engineered Myc mutations Less...