Amplification of MYCN is a driver of neuroblastoma development, necessitating strategies to target the protein for effective therapy. The N-MYC protein, like its counterpart, MYC, is a globally acting transcription factor that binds to virtually all active promoters and thousands of enhancers. Current data show that MYC proteins have unusual and potentially targetable ways to engage the transcription machinery. For example, we have recently shown that a critical domain in MYC (MycBoxI) recruits the PAF1c transcription elongation complex to promoters and catalyzes a Brd4- and Cdk9-dependent transfer of PAF1c onto RNA polymerase, providing a model how bromodomain and Cdk inhibitors can target MYC-dependent transactivation .
In neuroblastoma, N-MYC is stabilized by association with the Aurora-A protein. As a consequence, Aurora-A ligands that disrupt the complex destabilize N-MYC. This strategy shows therapeutic efficacy in mouse models of several N-MYC driven tumors and in (c)MYC-driven hepatocellular carcinoma and is being explored in human clinical trials. In contrast, the biological function of the N-MYC/Aurora-A complex has not yet been clarified. We have therefore purified N-MYC protein complexes from neuroblastoma cells and identified novel co-activator complexes that link N-MYC with proteins involved in chromatin topology. These co-activator complexes are specifically required for activation of cell cycle regulated target genes by N-MYC. Association of N-MYC with Aurora-A remodels the co-activator complexes during progression through the cell cycle, arguing that the regulated association of N-MYC with Aurora-A links N-MYC function with the cell cycle machinery. We will present these findings and discuss how they may open new strategies to target N-MYC function.