title: Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD.
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.
authors: Department of Internal Medicine, Kidney Institute.
authors: Xia
authors: X
authors: Zhou
authors: Department of Internal Medicine, Kidney Institute.
authors: Lucy X
authors: LX
authors: Fan
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Dorien J M
authors: DJ
authors: Peters
authors: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Université de Montreal, Faculté de Médecine, Montreal, Quebec, Canada and.
authors: Marie
authors: M
authors: Trudel
authors: Department of Medicine, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors: James E
authors: JE
authors: Bradner
authors: Department of Internal Medicine, Kidney Institute, Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA, xli3@kumc.edu.
authors: Xiaogang
authors: X
authors: Li
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D003560:Cysts / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000628:therapy*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D009687:Nuclear Proteins; D011493:Protein Kinase C; D016271:Proto-Oncogene Proteins c-myc; D050396:TRPP Cation Channels; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C089212:protein kinase D