BET Bromodomain as a Target of Epigenetic Therapy

Noguchi‐Yachide, Tomomi

doi:10.1248/cpb.c16-00225

Cited by 52 publications

(26 citation statements)

References 54 publications

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“…Bromodomain and extra-terminal (BET) domain inhibitors are currently under clinical trial for the treatment of various cancers [75]. These drugs target proteins with a bromodomain, which recognises acetylated histone marks.…”

Section: Relevance To Breast Cancermentioning

confidence: 99%

Epigenomics of mammary gland development

et al. 2018

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Differentiation of stem cells into highly specialised cells requires gene expression changes brought about by remodelling of the chromatin architecture. During this lineage-commitment process, the majority of DNA needs to be packaged into inactive heterochromatin, allowing only a subset of regulatory elements to remain open and functionally required genes to be expressed. Epigenetic mechanisms such as DNA methylation, post-translational modifications to histone tails, and nucleosome positioning all potentially contribute to the changes in higher order chromatin structure during differentiation. The mammary gland is a particularly useful model to study these complex epigenetic processes since the majority of its development is postnatal, the gland is easily accessible, and development occurs in a highly reproducible manner. Inappropriate epigenetic remodelling can also drive tumourigenesis; thus, insights into epigenetic remodelling during mammary gland development advance our understanding of breast cancer aetiology. We review the current literature surrounding DNA methylation and histone modifications in the developing mammary gland and its implications for breast cancer.

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Section: Relevance To Breast Cancermentioning

confidence: 99%

Epigenomics of mammary gland development

et al. 2018

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“…BRD4, a well-reported member of the BET family, is generally expressed as a nuclear protein that binds to acetylated lysine residues on histones via its bromodomains ( 9 ). BRD4 recruits chromatin remodeling and transcription factors, as well as other associated proteins, such as positive transcription elongation factor b, to specific transcriptional sites, this leads to transcription elongation via the modulation of RNA polymerase II ( 9 , 10 ). BRD4 also interacts with RelA, a subunit of the nuclear factor-κB transcriptional complex, inducing an inflammatory response ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…BRD4 recruits chromatin remodeling and transcription factors, as well as other associated proteins, such as positive transcription elongation factor b, to specific transcriptional sites, this leads to transcription elongation via the modulation of RNA polymerase II ( 9 , 10 ). BRD4 also interacts with RelA, a subunit of the nuclear factor-κB transcriptional complex, inducing an inflammatory response ( 10 ). BRD4 has been reported to serve vital roles in cell proliferation and cardiac hypertrophy ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…BRD4 also interacts with RelA, a subunit of the nuclear factor-κB transcriptional complex, inducing an inflammatory response ( 10 ). BRD4 has been reported to serve vital roles in cell proliferation and cardiac hypertrophy ( 9 , 10 ). In addition, the aberrant expression of BRD4 has been frequently reported in a variety of diseases, such as cancer ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression

Tan

Wang

et al. 2018

Int J Oncol

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Prostate cancer (PCa) is a malignant tumor with a high incidence in males. Localized tumors can be treated via surgery or radiation; however, it remains difficult to prevent disease progression. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader protein that binds to acetylated lysine on histones and has been reported to serve critical roles in numerous types of cancers. In the present study, it was demonstrated that BRD4 expression levels were significantly increased in cancerous prostate tissue specimens and cells, which were associated with clinical stage and metastasis. In addition, the present study reported that inhibition of BRD4 via short hairpin RNA or JQ1 (a bromo-domain inhibitor) decreased PCa cell proliferation, induced G0/G1 cell cycle arrest and apoptosis, mitigated cell invasion and migration in vitro, and impaired tumor growth in vivo. Mechanistically, BRD4 inhibition-induced suppression of cell cycle progression was associated with the upregulation of p21 and cyclin D1. c-Myc and B-cell lymphoma-2 (Bcl-2), important genes responsible for cell cycle regulation and anti-apoptotic functions, were downregulated in response to BRD4 inhibition. Furthermore, the present study revealed that c-Myc expression was negatively regulated by p21, and that the induction of p21 via BRD4 inhibition was mediated by forkhead box protein O1 (FOXO1), rather than p53. In summary, the results of the present study suggested that the aberrant expression of BRD4 in PCa may induce carcinogenesis. In addition, a mechanism by which BRD4 inhibition suppresses cell proliferation via the regulation of FOXO1-p21-Myc signaling was proposed in the present study, which may contribute to the development of novel therapeutic approaches in the management of PCa.

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“…In addition, BRD4 has been reported to bind acetylated lysine in NF‐κB and regulate its transcriptional activity, causing inflammation and cancer progression . Therefore, BRD4 is considered as a target for the treatment of cancer or inflammatory diseases . BRDT has particularly interesting features, although reports on its biology are limited .…”

Section: Application Of Protacs To Epigenetic Targetsmentioning

confidence: 99%

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Itoh

2018

The Chemical Record

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In addition to traditional drugs, such as enzyme inhibitors, receptor agonists/antagonists, and protein-protein interaction inhibitors as well as genetic technology, such as RNA interference and the CRISPR/Cas9 system, protein knockdown approaches using proteolysis-targeting chimeras (PROTACs) have attracted much attention. PROTACs, which induce selective degradation of their target protein via the ubiquitin-proteasome system, are useful for the down-regulation of various proteins, including disease-related proteins and epigenetic proteins. Recent reports have shown that chemical protein knockdown is possible not only in cells, but also in vivo and this approach is expected to be used as the therapeutic strategy for several diseases. Thus, this approach may be a significant technique to complement traditional drugs and genetic ablation and will be more widely used for drug discovery and chemical biology studies in the future. In this personal account, a history of chemical protein knockdown is introduced, and its features, recent progress in the epigenetics field, and future outlooks are discussed.

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BET Bromodomain as a Target of Epigenetic Therapy

Cited by 52 publications

References 54 publications

Epigenomics of mammary gland development

Epigenomics of mammary gland development

Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

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