Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance

Abstract

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.

Integrated requirement of non-specific and sequence-specific DNA binding in MYC-driven transcription

“…Altogether, Myc HEA lacks E-box recognition but retains the propensity to distribute along active chromatin when overexpressed, consistent with the notion that chromatin features (i.e. accessibility, composition, protein-protein interactions, etc…) rather than DNA sequence are the primary determinants of Myc binding (Guccione et al, 2006, Kim et al, 2008, Richart et al, 2016, Soufi et al, 2012, Thomas et al, 2019, Thomas et al, 2015. However, binding must also rely upon close contacts with the DNA backbone, as demonstrated by the loss of interaction seen with the Myc RA mutant.…”

“…Myc dimerizes with Max (Blackwood & Eisenman, 1991) to bind DNA with a preference for the E-box consensus sequence CACGTG (Blackwell et al, 1993, Solomon et al, 1993, through which it activates transcription (Amati et al, 1992, Kretzner et al, 1992. Within cells, however, Myc promiscuously associates with active chromatin (Guccione et al, 2006, Kim et al, 2008, Soufi et al, 2012, owing most likely to a combination of general accessibility , protein-protein interactions (Richart et al, 2016, Thomas et al, 2019, Thomas et al, 2015 and non-specific DNA binding (Brownlie et al, 1997, Ferre-D'Amare et al, 1993, Nair & Burley, 2003, Sauvé et al, 2007:…”

Targeting MYC through WDR5

“…we reasoned, then MYC should be evicted with it at co-bound genes. Indeed, we showed that WIN site inhibition is as effective at displacing MYC from chromatin at protein synthesis genes as genetic disruption of the MYC-WDR5 interaction 10 a manipulation that, as mentioned above, causes rapid and complete tumor loss. The effect of WIN site inhibitors on recruitment of MYC to chromatin is a notable advance with real practical consequences: The WIN site of WDR5 is much more druggable than the MYC site, and there are several groups that have distinct WIN site inhibitors thatin light of our recent workcould be repurposed for targeting MYC.…”

“…Our recent studies have begun to overcome these obstacles. 8,9,10 In our most recent paper, 10 we studied the MYC-WDR5 connection in the context of Burkitt lymphoma, which is driven by a chromosomal translocation that places MYC expression under control of a potent immunoglobulin heavy chain enhancer. We learned that MYC and WDR5 co-bind to a fairly small group of genes that are manifestly connected to protein synthesis, including those encoding more than half of the proteins in the ribosome.…”

“…9 These molecules require further refinement before extensive cell-or animalbased testing can begin. But for those who read our Burkitt lymphoma study closely, 10 there is a strong sign that MYC-site inhibitors may not be absolutely needed to target MYC through WDR5.…”