Targeting the epigenetic reader ENL inhibits super-enhancer-driven oncogenic transcription and synergizes with BET inhibition to suppress tumor progression.

Epigenetic alterations at cis-regulatory elements (CREs) fine-tune transcriptional output. Epigenetic readers interact with CREs and can cooperate with other chromatin regulators to drive oncogene transcription. Here, we found that the YEATS domain-containing histone acetylation reader ENL (eleven-nineteen leukemia) acts as a key regulator of super-enhancers (SEs), which are highly active distal CREs, across cancer types. ENL occupied the majority of SEs with substantially higher preference over typical-enhancers, and the enrichment of ENL at SEs depended on its ability to bind acetylated histones. Rapid depletion of ENL by auxin-inducible degron tagging severely repressed the transcription of SE-controlled oncogenes, such as MYC, by inducing the decommissioning of their SEs, and restoring ENL protein expression largely reversed these effects. Additionally, ENL was indispensable for the rapid activation of SE-regulated immediate early genes in response to growth factor stimulation. Furthermore, ENL interacted with the histone chaperone FACT complex and was required for the deposition of FACT over CREs, which mediates nucleosome reorganization required for transcription initiation and elongation. Proper control of transcription by ENL and ENL-associated FACT was regulated by the histone reader BRD4. ENL was overexpressed in colorectal cancer (CRC) and functionally contributed to CRC growth and metastasis. ENL degradation or inhibition synergized with BET inhibitors that target BRD4 in restraining CRC progression. These findings establish the essential role of epigenetic reader ENL in governing SE-driven oncogenic transcription and uncover the potential of ENL intervention to increase sensitivity to BET inhibition.