Amplification of MED30 at chromosome 8q24 reprograms MYC binding to low-affinity oncogenic enhancers in cancer cells

The activity of many oncogenic transcription factors (TFs) is constrained by enhancer binding-site affinity, leaving many low-affinity sites unoccupied under physiological conditions. Whether coactivator amplification in cancer redirects TFs to these sites is unclear. Here, we show that amplification of MED30, a Mediator subunit at 8q24, promotes aberrant MYC binding to low-affinity regulatory regions and is associated with poor outcomes. Besides frequent MYC MED30 co-amplification, MED30 overexpression alone is sufficient to enable MYC occupancy and activation of previously weak or unbound enhancers and promoters, driving tumor-promoting gene expression. Functional studies in pancreatic ductal adenocarcinoma and glioblastoma demonstrate that MED30 is oncogenic and serves as a prognostic marker independent of MYC amplification. These findings reveal a cofactor-driven mechanism by which MED30 licenses MYC binding to low-affinity sites, reprogramming enhancers during cancer progression with therapeutic implications.