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.