The mechanisms behind the therapeutic activity of BET bromodomain inhibition

By Junwei Shi, C. Vakoc. Molecules and Cells, 2014

854 citations recorded by the source corpus.

The bromodomain and extra-terminal (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 subset 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 pharmacological BET bromodomain inhibition.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bb54b1c81bd2eedb626fbbfdf1826a7a6158f704

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

1. Richard A. Young
2. B. Donati
3. James E. Bradner
4. Denes Hnisz
5. Eugenia Lorenzini
6. A. Ciarrocchi

In Molecular Biology

1. Denes Hnisz
2. C. Crews
3. Richard A. Young
4. James E. Bradner
5. B. Donati
6. Eugenia Lorenzini
7. A. Ciarrocchi
8. Tong Ihn Lee

Citations in the corpus

• Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. (2015, background): “BRD4 belongs to the bromodomain and extraterminal domain (BET) family of proteins, which is characterized by two bromodomains (BD) at the N terminus and an extraterminal domain (ET domain) at the C terminus (Belkina and Denis, 2012; Shi and Vakoc, 2014).”
• PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer (2016, background): “Given these emerging data, and because BET family proteins are known to have scaffolding functions whereby they interact with a variety of transcriptional regulators through their extraterminal and C-terminal domains (41, 42), we hypothesized that a BET degrader would have a more profound effect tha”
• BRD4 and Cancer: going beyond transcriptional regulation (2018, methodology): “As well, ChIP seq data showed that BRD4 occupies many ENHs and promoters also in non-cancer cells and generally contributes to gene expression (Table 1) [6].”
• Transcriptional Addiction in Cancer (2017, positive): “…TFs acquire especially large SEs, with exceptionally high densities of enhancer factors, and this may further contribute to the exceptional vulnerability of SEdriven oncogenic TFs seen with inhibition of BRD4 (Bhagwat et al., 2016; Chapuy et al., 2013; Loven et al., 2013; Shi and Vakoc, 2014).”