Abstract The transcription factor c-MYC (MYC) is deregulated in ~70% of human cancers. Through de novo motif discovery analysis on published MYC ChIP-seq datasets from cancer cell lines, we found cell-type-specific co-enrichment of the TRE motifs (AP-1 binding sites) alongside MYC’s canonical EBOX motif. MYC binds indirectly to TRE motifs in cooperation with AP-1 transcription factors, and these indirect interactions occur predominantly at enhancers rather than promoters. At elevated MYC levels, as seen in cancers, MYC’s indirect binding to TRE sites at enhancers increases. Integration of ChIP-seq and RNA sequencing data revealed that TRE enhancer-binding sites are frequently associated with MYC-mediated transcriptional repression. Gene Ontology analysis showed that MYC utilizes TRE sites to transcriptionally rewire cells, modulating cancer hallmarks like proliferation, apoptosis, and cell adhesion. These molecular insights into how increased MYC levels alter gene regulation could inform new therapeutic strategies targeting cancer-specific MYC functions and its co-regulators.
Sundaram et al. (Thu,) studied this question.