Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD

Xia Zhou, Lucy X. Fan, Dorien J.M. Peters, Marie Trudel, James E. Bradner, Xiaogang Li

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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.

Original languageEnglish (US)
Article numberddv136
Pages (from-to)3982-3993
Number of pages12
JournalHuman Molecular Genetics
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Zhou, X., Fan, L. X., Peters, D. J. M., Trudel, M., Bradner, J. E., & Li, X. (2015). Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD. Human Molecular Genetics, 24(14), 3982-3993. [ddv136]. https://doi.org/10.1093/hmg/ddv136