Role of Host Cell Factor-1 in MYC-driven gene expression and tumorigenesis
Popay, Tessa Mary
The oncoprotein transcription factor MYC is a major driver of malignancy and a highly-validated target for development of anti-cancer therapies. It has, however, proven challenging to inhibit MYC directly. Novel strategies to inhibit MYC may come from understanding the cofactors it uses to drive pro-tumorigenic gene expression programs, providing their role in MYC activity is understood. Here, I examine the molecular elements defining the interaction between MYC and the transcriptional regulator Host Cell Factor (HCF)-1, and interrogate how their association contributes to MYC function in the context of Burkitt lymphoma (BL). I find that the mode of interaction between MYC and HCF-1 is sub-optimal, and that mutation of their interaction surface in MYC can be used to either decrease or increase their association in the BL setting. Using inducible systems for expression of these loss- and gain-of-function MYC mutants and degradation of HCF-1, I identify genes responsible for ribosome biogenesis, translation, and mitochondrial function as direct targets for activation by the MYC–HCF-1 interaction. Disruption of this interaction and the resulting impact on expression of target genes leads to reduced cell growth and glutamine dependency, altered metabolite profiles, and compensatory gene expression patterns. When BL cells are introduced into the flanks of mice, disruption to the MYC–HCF-1 interaction manifests as impaired tumor growth, both in the context of engraftment and maintenance. This work defines HCF-1 as a critical MYC cofactor, places the MYC–HCF-1 interaction in a biological context, and highlights HCF-1 as a focal point for development of novel anti-MYC therapies.