BRD4 inhibitors block telomere elongation

Nucleic Acids Res. 2017 Aug 21;45(14):8403-8410. doi: 10.1093/nar/gkx561.

Abstract

Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.

MeSH terms

  • Acetanilides / pharmacology
  • Animals
  • Azepines / pharmacology
  • Blotting, Southern
  • Cell Cycle Proteins
  • Cell Line
  • Dose-Response Relationship, Drug
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression / drug effects
  • HeLa Cells
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mice
  • Morpholines / pharmacology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pyrones / pharmacology
  • RNA Interference
  • Telomerase / genetics
  • Telomerase / metabolism
  • Telomere / drug effects
  • Telomere / enzymology
  • Telomere / genetics
  • Telomere Homeostasis / drug effects
  • Telomere Homeostasis / genetics*
  • Telomere Shortening / drug effects
  • Telomere Shortening / genetics*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
  • Acetanilides
  • Azepines
  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • GSK1210151A
  • Heterocyclic Compounds, 3-Ring
  • Heterocyclic Compounds, 4 or More Rings
  • Morpholines
  • Nuclear Proteins
  • OTX015
  • Pyrones
  • Transcription Factors
  • Triazoles
  • Telomerase