The mechanisms behind the therapeutic activity of BET bromodomain inhibition

Mol Cell. 2014 Jun 5;54(5):728-36. doi: 10.1016/j.molcel.2014.05.016.

Abstract

The bromodomain and extraterminal (BET) protein Brd4 recruits transcriptional regulatory complexes to acetylated chromatin. While Brd4 is considered to be a general transcriptional regulator, pharmacological inhibition of BET proteins shows therapeutic activity in a variety of different pathologies, particularly in models of cancer and inflammation. Such effects have been attributed to a specific set of downstream target genes whose expression is disproportionately sensitive to pharmacological targeting of BET proteins. Emerging evidence links the transcriptional consequences of BET inhibition to the association of Brd4 with enhancer elements, which tend to be involved in lineage-specific gene regulation. Furthermore, Brd4 engages in direct regulatory interactions with several DNA-binding transcription factors to influence their disease-relevant functions. Here we review the current understanding of molecular mechanisms that underlie the promising therapeutic effects of BET bromodomain inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Cycle Proteins
  • Gene Expression Regulation
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism

Substances

  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • BRD2 protein, human
  • BRD3 protein, human
  • BRD4 protein, human
  • BRDT protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • Protein-Serine-Threonine Kinases