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BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer
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BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer
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Journal Article
BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer
2022
Overview
BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2. 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 genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex–restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in superenhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.
Publisher
National Academy of Sciences
Subject
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - metabolism
/ Cell Cycle Proteins - genetics
/ Cell Cycle Proteins - metabolism
/ Female
/ Genes
/ Histone Demethylases - genetics
/ Histone Demethylases - metabolism
/ Humans
/ Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics
/ Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Transcription Factors - genetics
