The core transcriptional regulatory program governed by a small set of master transcription factors is pivotal for establishing context-specific cellular features, as has been elegantly illustrated in embryonic stem cells. However, the core regulatory program in prevalent malignancies like colorectal cancer (CRC) remained elusive. Here, we reported uncharted roles of master factor MYC in actively regulating cancer-type specific super-enhancer (SE) activity and orchestrating a SE-dependent core transcriptional regulatory circuitry consisting of MYC, ETS2, and FOXP1 in CRC. The core regulatory module selectively promoted the transcription of SE-controlled genes through facilitating histone acetylation and BRD4 deposition at SEs, and perturbing the core factors sensitized CRC cells to BET inhibition. Notably, a key stemness gene LGR5 was activated in CRC by a circuitry-controlled distal SE, which was one of the most significantly gained CRC-specific SEs and was required for propagating liver metastases of CRC. Lgr5 transcription in intestinal stem cells was likewise sustained by Myc through enhancer regulation, highlighting the possibility that MYC overactivation hijacks normal regenerative program of intestine for oncogenic transformation. These findings reveal a hierarchical transcription regulatory network in CRC, pinpoint distal enhancer as an important fuel for LGR5 overexpression in cancer, and provide insights for precisely targeting detrimental transcription events in CRC therapy.
王石蓝(Shilan Wang) (Thu,) studied this question.