Kalyan Sundaram, R.; Radhakrishnan, R.; Lim, B.

The transcription factor c-MYC (MYC) is deregulated in about 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. TRE motifs serve as indirect MYC binding sites in synergy with AP-1, predominantly at enhancers rather than promoters. At elevated MYC levels, as seen in cancers, MYC preferentially occupies TRE sites over EBOX sites at enhancers. Integration of ChIP-seq and RNA-seq data revealed 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 its DNA binding preference and gene regulation could inform new therapeutic strategies targeting cancer-specific MYC functions and its co-regulators.