biostudies-literatureLiu BMinistry of Science and Technology of the People''''s Republic of ChinaNational Natural Science Foundation of Chinae2109133119https://www.ebi.ac.uk/biostudies/studies/S-EPMC8832982biostudies-literatureUnknown119(6)BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including <i>c-MYC</i> and <i>BCL2</i> As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant geneProceedings of the National Academy of Sciences of the United States of AmericaBRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer.PMC883298281730079319911641302304Liu XWu JHan LZhang YShan LYan DShang YLiu BChen XLiu SWang YWu XfalseBRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer.BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including <i>c-MYC</i> and <i>BCL2</i> As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant gene2022-01-01T00:00:00Z2022 Feb2026-06-18T05:59:34.59Z2025-04-05T20:07:22.845ZS-EPMC88329823510580310.1073/pnas.2109133119