ArticleCancer medicine2013
BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1.
Article in Cancer medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 86 citations in OpenAlex.
- BRD4-mediated transcriptional activation of PDLIM4 enhances p21 stability and chemosensitivity in lung adenocarcinoma independent of p53.BMC biology · 2026Article
- Novel BRD4-p53 Inhibitor SDU-071 Suppresses Proliferation and Migration of MDA-MB-231 Triple-Negative Breast Cancer Cells.ACS pharmacology & translational science · 2024Article
- BET in hematologic tumors: Immunity, pathogenesis, clinical trials and drug combinations.Genes & diseases · 2023Review
- BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer.Cancers · 2023Article
- Alternatively mechanistic insights into acetylation in p53-mediated transcriptional regulation of cancer cell-intrinsic PD-1.Fundamental research · 2023Article
- Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Regulation of programmed cell death by Brd4.Cell death & disease · 2022Review
- Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression.International journal of molecular sciences · 2022Article
- NSMCE2, a novel super-enhancer-regulated gene, is linked to poor prognosis and therapy resistance in breast cancer.BMC cancer · 2022Article
- HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents' combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model.Medical oncology (Northwood, London, England) · 2022Article
- Phosphoproteomics Reveals the AMPK Substrate Network in Response to DNA Damage and Histone Acetylation.Genomics, proteomics & bioinformatics · 2022Article
- Article
- Deciphering the PTM codes of the tumor suppressor p53.Journal of molecular cell biology · 2022Review
- The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells.HemaSphere · 2021Article
- Simplicity is the Ultimate Sophistication-Crosstalk of Post-translational Modifications on the RNA Polymerase II.Journal of molecular biology · 2021Review
- Gene Transcription as a Therapeutic Target in Leukemia.International journal of molecular sciences · 2021Review
- BRD4-mediated repression of p53 is a target for combination therapy in AML.Nature communications · 2021Article
- Article
- Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and CaInternational journal of molecular sciences · 2020Article
- The role of enhancer RNAs in epigenetic regulation of gene expression.Transcription · 2020Review
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53-mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein-protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease.
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