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PMID: 24905006 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

The mechanisms behind the therapeutic activity of BET bromodomain inhibition.

Molecular cell ·Vol. 54 ·No. 5 ·2014-06-05 ·Pages 728-36

Shi J, Vakoc CR

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.

MeSH Terms
Animals Anti-Inflammatory Agents/pharmacology,therapeutic use Antineoplastic Agents/pharmacology,therapeutic use Cell Cycle Proteins Gene Expression Regulation Humans Inflammation/drug therapy,metabolism Molecular Targeted Therapy Neoplasms/drug therapy,metabolism Nuclear Proteins/antagonists & inhibitors,metabolism Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism Protein Structure, Tertiary RNA-Binding Proteins/antagonists & inhibitors,metabolism Transcription Factors/antagonists & inhibitors,metabolism
Chemicals
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
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Shi Junwei
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
Vakoc Christopher R
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2014.05.016
Email
vakoc@cshl.edu
Published
2014-06-05
Pages
728-36
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC4236231
Subset
IM
Grants
NCI NIH HHS · R01 CA174793 · United States
NCI NIH HHS · CA174793 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2014.05.016 PMC Full Text View journal details
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