The emerging role of BET inhibitors in breast cancer

Andrikopoulou, Αngeliki; Liontos, Michalis; Koutsoukos, Konstantinos; Dimopoulos, Meletios-Athanasios; Zagouri, Flora

doi:10.1016/j.breast.2020.08.005

Cited by 38 publications

(27 citation statements)

References 111 publications

(219 reference statements)

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“… 53 In clinical trials, it has been found that thrombocytopenia is the most important toxicity of BET inhibitors; gastrointestinal diseases, anemia, and fatigue are the most common adverse events related to BET inhibitor treatment. 54 The combination of JQ1 and other drugs can not only enhance the efficacy but also effectively inhibit the side effects of drug treatment. 55 , 56 Our research shows that BRD4 can regulate the growth of melanoma cells through the mitochondrial pathway and that BRD4 inhibition impairs the mitochondrial function of B16 cells, leading to energy metabolism dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Although JQ1 has become a research hotspot in the last five years due to its highly specific recognition site, good cell permeability, and low toxic and side effects, its short half‐life may lead to increased toxicity and side effects of the drug, which limits its clinical application 53 . In clinical trials, it has been found that thrombocytopenia is the most important toxicity of BET inhibitors; gastrointestinal diseases, anemia, and fatigue are the most common adverse events related to BET inhibitor treatment 54 . The combination of JQ1 and other drugs can not only enhance the efficacy but also effectively inhibit the side effects of drug treatment 55,56 .…”

Section: Discussionmentioning

confidence: 99%

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Bromodomain‐containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics

Meng

et al. 2021

Cancer Science

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Melanoma is one of the most malignant skin tumors. The SEER database (http://seer.cancer.gov/statf acts/ht) reports that there were more than 192 000 new invasive melanoma skin cancer cases in 2019, making it the fifth most common cancer. Although early melanoma can be effectively treated by surgery and targeted therapies and small molecule inhibitors for melanoma have been successfully developed, 1 the prognosis of the disease remains poor. Therefore, a better understanding of the pathogenesis of melanoma is urgently needed to enable new ideas for the treatment of these patients.Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) protein family. As a transcriptional and epigenetic regulatory factor, BRD4 plays a key role in embryogenesis and cancer development. 2,3 JQ1 is a small molecule inhibitor targeting BRD4 that displaces the protein from chromatin by mimicking acetyl groups and binding to the acetyllysine pocket. JQ1 exerts its antitumor effects by regulating the

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bromodomain‐containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics

Meng

et al. 2021

Cancer Science

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“…Bromodomain proteins can further be subdivided into two families, the BET and non-BET families, on the basis of their structural parameters [ 46 ]. BET proteins are directly associated with transcription and maintaining the effective progression of the cellular cycle [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

Sun

Zhao

et al. 2021

Cell Death Dis

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Gastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3β/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3β/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.

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“…This led to the prediction that using bromodomain inhibitors in addition to the standard therapy may reduce the development of resistance in some cancers [ 313 ]. Combinations of epigenetic therapeutics have also proven successful in the treatment of acute myeloid leukemia [ 314 ], multiple myeloma [ 315 ], pancreatic cancer [ 316 ], ovarian cancer [ 317 ], and in breast cancer [ 318 ]. One mechanism for this synergy has been outlined through the dual inhibition of BET bromodomains in combination with poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi).…”

Section: Emerging Strategies To Target Bromodomain Proteinsmentioning

confidence: 99%

Functional Roles of Bromodomain Proteins in Cancer

Boyson

Gao

Quinn

et al. 2021

Cancers

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Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.

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The emerging role of BET inhibitors in breast cancer

Cited by 38 publications

References 111 publications

Bromodomain‐containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics

Bromodomain‐containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

Functional Roles of Bromodomain Proteins in Cancer

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