A core transcriptional regulatory circuitry controls super-enhancer-driven activation of LGR5 in colorectal cancer

The core transcriptional regulatory program governed by a small set of master transcription factors is pivotal for establishing context-specific cellular features. Here, we report the roles of master factor MYC in actively regulating cancer-type specific super-enhancer activity and orchestrating a super-enhancer-dependent core transcriptional regulatory circuitry consisting of MYC, ETS2, and FOXP1 in colorectal cancer. The core regulatory module selectively promotes the transcription of super-enhancer-controlled genes in cooperation with co-activator BRD4, and perturbing the core circuitry factors sensitizes colon cancer cells to BET inhibition. LGR5, a key stemness gene, is activated in colorectal cancer at least in part by a circuitry-controlled distal super-enhancer, which is a frequently gained super-enhancer in colorectal cancer and required for metastasis propagation. These findings reveal a hierarchical transcription regulatory network in colorectal cancer, pinpoint distal enhancer as an important fuel for LGR5 overexpression in cancer, and provide insights for precisely targeting detrimental transcription events in therapy. MYC can be transcriptionally regulated by distal super-enhancers (SEs) in cancers. Here, the authors show that MYC, along with ETS2 and FOXP1, form a core regulatory circuit that controls SE-driven transcription in colorectal cancer.