BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition

Andrieu, Guillaume P.; Denis, Gerald V.

doi:10.1158/1541-7786.mcr-17-0568

Cited by 47 publications

(46 citation statements)

References 23 publications

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“…Since ZNF281 is involved in inducing epithelial–mesenchymal transition (EMT) and promotes metastatis [52], anti-oncogenic effects of JQ1 on H23 cells may partly be due to downregulation of ZNF281, presumably through dissociation of BRD2, which may lead to disrupted EMT in lung cancer. Interestingly, a recent study showed that BRD2 activates expression of genes involved in EMT induction, whereas BRD3 and BRD4 exert opposite functions [53], supporting distinct roles of BRD2 among the somatic BET proteins [34,35,54,55]. Other TFs identified by MARA but not discussed here may be involved in the BRD2-associated transcriptional regulation.…”

Section: Discussionmentioning

confidence: 54%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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Section: Discussionmentioning

confidence: 54%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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“…Consistent with this notion, the combination of BET bromodomain inhibitor JQ1 and TKIs has been suggested to be a rational strategy for treating leukemia and lymphoma . Additionally, BRD2 was shown to positively control epithelial‐mesenchymal transition in breast cancer, and a GS for this histologic transformation could forecast the resistance to EGFR inhibitor erlotinib in both wild‐type EGFR and mutant EGFR lung cancer cases …”

Section: Discussionmentioning

confidence: 89%

Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD‐L1 immunotherapy

Hwang

2019

Cancer Medicine

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The overall survival rates for lung cancer remain unsatisfactorily low, even for patients with biomarkers for which target therapies or immunotherapies are recommended. Better identification of at‐risk patients is needed to achieve more effective personalized treatment. Here, we derived a risk‐stratifying gene signature consisting of five genes that had the greatest differential expression by stage from lung adenocarcinoma (LUAD) transcriptomes. The new gene signature enabled survival prognosis for multiple LUAD datasets from different platforms of transcriptomics and risk stratification for patients with and without a mutation in TP53 or EGFR, with high and low levels of PD‐L1, and with and without adjuvant chemotherapy treatment. Using these evaluations, it was also shown to be more robust compared to several other gene signatures. Functional analysis of the five genes and their protein‐protein interaction partners indicated that they are functionally enriched in cell cycle, endocytosis, and EGFR regulation, which are biological processes associated with lung cancer and drug resistance. Extensive discussions on related experimental studies suggest that the five genes are novel and sensible targets for developing new drugs and/or tackling drug resistance problems for LUAD.

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“…Among the different mechanisms of action, BETi have been found to play a role as regulators of self-renewal and stem cell signalling in some cancers, including medulloblastoma and head and neck squamous cell carcinoma [27,28]. Although several studies have investigated the impact of BET protein inhibition in breast cancer [29][30][31][32][33], some of them evaluating its impact on epithelial-to-mesenchymal transition [34], little is known about the impact of their associated epigenetic drugs on cancer stemness in this cancer type. Here, we show how the BETi JQ1 alters the genetic stemness landscape, together with its associated features, and identify a stemnessrelated gene panel associated with BET inhibition in TNBC.…”

Section: Discussionmentioning

confidence: 99%

Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer

et al. 2020

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Purpose Triple negative breast cancers (TNBCs) are enriched in cells bearing stem-like features, i.e., cancer stem cells (CSCs), which underlie cancer progression. Thus, targeting stemness may be an interesting treatment approach. The epigenetic machinery is crucial for maintaining the stemness phenotype. Bromodomain and extra-terminal domain (BET) epigenetic reader family members are emerging as novel targets for cancer therapy, and have already shown preclinical effects in breast cancer. Here, we aimed to evaluate the effect of the BET inhibitor JQ1 on stemness in TNBC. Methods Transcriptomic, functional annotation and qRT-PCR studies were performed on JQ1-exposed TNBC cells in culture. The results obtained were confirmed in spheroids and spheroid-derived tumours. In addition, limiting dilution, secondary and tertiary tumour sphere formation, matrigel invasion, immunofluorescence and flow cytometry assays were performed to evaluate the effect of JQ1 on CSC features. For clinical outcome analyses, the online tool Kaplan-Meier Plotter and an integrated response database were used. Results We found that JQ1 modified the expression of stemness-related genes in two TNBC-derived cell lines, MDA-MB-231 and BT549. Among these changes, the CD44 Antigen/CD24 Antigen (CD44/CD24) ratio and Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) expression level, i.e., both classical stemness markers, were found to be decreased by JQ1. Using a validated spheroid model to mimic the intrinsic characteristics of CSCs, we found that JQ1 decreased surface CD44 expression, inhibited self-renewal and invasion, and induced cell cycle arrest in G0/G1, thereby altering the stemness phenotype. We also found associations between four of the identified stemness genes, Gap Junction Protein Alpha 1 (GJA1), CD24, Epithelial Adhesion Molecule (EPCAM) and SRY-related HMG-box gene 9 (SOX9), and a worse TNBC patient outcome. The expression of another two of the stemness-related genes was found to be decreased by JQ1, i.e., ATP Binding Cassette Subfamily G Member 2 (ABCG2) and RUNX2, and predicted a low response to chemotherapy in TNBC patients, which supports a role for RUNX2 as a potential predictive marker for chemotherapy response in TNBC. Conclusions We identified a stemness-related gene panel associated with JQ1 and describe how this inhibitor modifies the stemness landscape in TNBC. Therefore, we propose a novel role for JQ1 as a stemness-targeting drug. Loss of the stem cell Leticia Serrano-Oviedo and Miriam Nuncia-Cantarero contributed equally to this work.

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BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition

Cited by 47 publications

References 23 publications

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD‐L1 immunotherapy

Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer

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