MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with Host Cell Factor-1
MYC is an oncoprotein transcription factor that is overexpressed in the majority cancers. Although MYC itself is considered undruggable, it may be possible to inhibit MYC by targeting the co-factors it uses to drive oncogenic gene expression patterns. Here, we use loss- and gain- of function approaches to interrogate how one MYC co-factor—Host Cell Factor (HCF)-1—contributes to MYC activity in a Burkitt lymphoma setting. We identify high-confidence direct targets of the MYC–HCF-1 interaction that are regulated through a recruitment-independent mechanism, including genes that control mitochondrial function and rate-limiting steps for ribosome biogenesis and translation. We describe how these gene expression events impact cell growth and metabolism, and demonstrate that the MYC–HCF-1 interaction is essential for tumor maintenance in vivo. This work highlights the MYC–HCF-1 interaction as a focal point for development of novel anti-cancer therapies. Overall design: The Burkitt lymphoma line Ramos cells was modified using CRISPR/Cas9-triggered homologous recombination to create either MYC switchable allele (MYC-WT, MYC-4A, MYC-VP16 HBM) or FKBP12FV N-terminally tagged HCF-1 cell lines. These cells were used for RNA-seq and ChIP-seq.