ArticleHuman molecular genetics2015
Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 59 citations in OpenAlex.
- BRD4-mediated transcriptional activation of PDLIM4 enhances p21 stability and chemosensitivity in lung adenocarcinoma independent of p53.BMC biology · 2026Article
- Engineered platelets as targeted protein degraders and application to breast cancer models.Nature biotechnology · 2025Article
- EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease.Journal of translational medicine · 2024Article
- Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.Cell stem cell · 2024Article
- MYC: there is more to it than cancer.Frontiers in cell and developmental biology · 2024Review
- Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression.International journal of molecular sciences · 2022Article
- Molecular Mechanisms of Epigenetic Regulation, Inflammation, and Cell Death in ADPKD.Frontiers in molecular biosciences · 2022Review
- Antioxidant enzyme peroxiredoxin 5 regulates cyst growth and ciliogenesis via modulating Plk1 stability.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.Frontiers in molecular biosciences · 2022Review
- Non-Coding RNAs in Hereditary Kidney Disorders.International journal of molecular sciences · 2021Review
- Super-enhancer-driven metabolic reprogramming promotes cystogenesis in autosomal dominant polycystic kidney disease.Nature metabolism · 2020Article
- Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex-associated cystic kidney disease.JCI insight · 2020Article
- Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury.Nature communications · 2020Article
- Epigenetics and cell cycle regulation in cystogenesis.Cellular signalling · 2020Review
- A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells.Scientific reports · 2020Article
- Heat-shock proteins: chaperoning DNA repair.Oncogene · 2020Review
- Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles.EBioMedicine · 2020Article
- Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease.Science advances · 2019Article
- Histone Deacetylase Inhibitors Reduce Cysts by Activating Autophagy in Polycystic Kidney Disease.Kidney diseases (Basel, Switzerland) · 2019Article
- c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis.Human molecular genetics · 2019Article
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Authors and funding
6 authors at 5 institutions in 4 countries.
Funding
Abstract
In this study, we identified a BET bromodomain (BRD) protein, Brd4, not only as a novel epigenetic regulator of autosomal dominant polycystic kidney disease (ADPKD) but also as a novel client protein of Hsp90. We found that Brd4 was upregulated in Pkd1 mutant mouse renal epithelial cells and tissues. This upregulation of Brd4 appears to result from the chaperone activity of Hsp90 and escape proteasomal degradation. We further identify that Brd4 is an upstream regulator of the expression of c-Myc which has been upregulated in all rodent models of PKD and ADPKD patients with unknown mechanism. Inhibition of Brd4 in Pkd1 mutant renal epithelial cells with JQ1, a selective small-molecular inhibitor of BET BRD protein(s), (1) decreased the levels of c-Myc mRNA and protein; (2) increased the levels of p21 mRNA and protein, which was transcriptionally repressed by c-Myc; (3) decreased the phosphorylation of Rb; and (4) decreased cystic epithelial cell proliferation as shown by inhibition of S-phase entry. Most importantly, treatment with JQ1 strikingly delayed cyst growth and kidney enlargement, and preserved renal function in two early stage genetic mouse strains with Pkd1 mutations. This study not only provides one of the mechanisms of how c-Myc is upregulated in PKD but also suggests that targeting Brd4 with JQ1 may function as a novel epigenetic approach in ADPKD. The unraveled link between Brd4 and Hsp90 in ADPKD may also be a general mechanism for the upregulation of Brd4 in cancer cells and opens up avenues for combination therapies against ADPKD and cancer.
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