BRD4 facilitates DNA damage response and represses CBX5/Heterochromatin protein 1 (HP1)

Pongas, Georgios; Kim, Marianne K.; Min, Dong Joon; House, Carrie D.; Jordan, Elizabeth; Caplen, Natasha J.; Chakka, Sirisha; Ohiri, Joyce C.; Kruhlak, Michael J.; Annunziata, Christina M.

doi:10.18632/oncotarget.17572

Cited by 25 publications

(20 citation statements)

References 31 publications

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“…In breast cancer, transcription factor Yin Yang 1(YY1) was suggested to be responsible for the reduced expression of HP1α [ 28 ]. In ovarian cancer, expression of HP1α was repressed by Bromodomain-containing protein 4 (BRD4), which defects DNA damage response to facilitate tumorigenesis [ 29 ]. Defective type III secretion mxiD Shigella flexneri strain can lead to more phosphorylation of HP1γ protein and regulated its activity, which might be related to the infections-controlled HP1γ protein.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression

Chen

Cheng

et al. 2018

IJMS

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Background: Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and function of CBX3 in PAAD. Methods: Data of transcriptomic and protein expression of CBX3 in PAAD were collected from different databases and analyzed. The in vitro and in vivo role of CBX3 in PAAD was examined. Results: CBX3 was overexpressed in human PAAD tissues, which was associated with poor prognosis of overall and disease-free survival of the patients. Overexpression of CBX3 induced the in vitro proliferation, anchorage-free growth, migration and invasion of the PAAD cells, and led to in vivo growth of orthotoptic PAAD tumors in mice. GO and KEGG pathway analysis, as well as experimental observation showed that CBX3 may be associated with cell cycle transition of PAAD cells, and cyclin-dependent kinase 1 (CDK1) and proliferating cell nuclear antigen (PCNA) may mediate the tumor-promoting action of CBX3. CDK1 knockdown attenuated the cell cycle transition, proliferation and invasion of CBX3-overexpressing PAAD cells. Conclusion: Our findings suggest the tumor-promoting role of CBX3 in PAAD to be targeted by novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression

Chen

Cheng

et al. 2018

IJMS

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“…We noted that BRD4 Y430C mESCs grew slower, and showed an accumulation of cells in G2/M (33.7%), compared to their WT counterparts (27.8%) (Figure 3A, B, Supplementary Figure 3A). This observation, together with the recently reported roles for BRD4 in the DDR and DNA repair 23–26 led us to investigate potential DDR defects in mutant cells.…”

Section: Resultsmentioning

confidence: 85%

Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Olley

Pradeepa

FitzPatrick

et al. 2019

Preprint

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Cornelia de Lange Syndrome is a multisystem developmental disorder typically caused by mutations in 51 the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be 52 the consequence of aberrant transcriptional regulation. Recently, we identified a residue substitution in 53 BRD4 associated with a Cornelia de Lange-like syndrome, that reduces BRD4 binding to acetylated 54 histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers in mouse 55 embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increases DNA 56 damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new role for 57 BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA 58 damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA 59 damage signalling and repair is also a feature of typical Cornelia de Lange Syndrome. 60 61 65 delayed growth 1 . CdLS is described as a 'cohesinopathy' 1 -most cases can be attributed to 66 heterozygous loss of function mutation in NIPBL encoding a protein involved in loading of the cohesin 67 complex onto chromatin 2 . Mutation in genes encoding cohesin complex proteins SMC1, SMC3 and 68 RAD21, or HDAC8 (SMC3 deacetylase), have also been identified in CdLS-like probands 2 . However 69 cells from CdLS patients have no obvious defects in sister chromatid cohesion 3 , and individuals with 70 mutations in SMC1, SMC3 and RAD21 are often considered 'atypical' in terms of facial appearance and 71 growth, and are less likely to have limb defects than those with NIPBL mutations 4 . 72Dysregulated gene expression has been proposed to be main mechanism underlying CDLS 5,6 . 73Mutations in genes encoding chromatin regulators unrelated to cohesin, such as ANKRD11, KMT2A, 74AFF4 and the bromodomain and extra-terminal domain (BET) protein BRD4, have been reported to 75 cause CdLS-like phenotypes 1 suggesting that chromatin dysregulation may play a role in CdLS as well. 76Additionally, increased sensitivity to DNA damage has been reported in CdLS patient cells 7 , but the 77 mechanism underlying this defect is unknown and its participation in the disease aetiology remains 78 unclear. 79Recently, we described de novo deletion and missense mutations in BRD4 associated with a clinical 80 phenotype overlapping CdLS 8 . BRD4 binds acetylated lysines residues in histones H3 and H4 through 81 its two N-terminal bromodomain domains (BD). BRD4 localises to promoters and enhancers of active 82 genes and is particularly enriched at super enhancers (SEs) 9,10 . BRD4 is a key regulator of transcription;; 83 through its C-terminal domain it recruits positive transcription elongation factor (P-TEFb) and the 84 Mediator complex to promoters and enhancers, whilst its extra-terminal domain confers transcriptional 85 activation through the recruitment of CHD4, JMJD6, and NSD3 11,12 . 86 3 The CdLS-associated BRD4 missense mutation is in the ...

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“…Dual-inhibition of BET and CHK1 resulted in significant apoptosis that was dependent on BRD4, but did not affect MYC protein levels. In vitro studies on ovarian cancer cells have also shown that therapy involving BET + CHK1 inhibition may be a promising treatment modality [96]. This study demonstrated that inhibition of BRD4 via siRNA or the BETi JQ1 increased heterochromatin protein 1 (HP1) in ovarian cancer cells which limited the DDR and increased sensitivity to CHK1i [96].…”

Section: Discussionmentioning

confidence: 92%

“…In vitro studies on ovarian cancer cells have also shown that therapy involving BET + CHK1 inhibition may be a promising treatment modality [96]. This study demonstrated that inhibition of BRD4 via siRNA or the BETi JQ1 increased heterochromatin protein 1 (HP1) in ovarian cancer cells which limited the DDR and increased sensitivity to CHK1i [96]. Studies are in progress to gain a detailed understanding of the underlying mechanisms of action contributing to the significant growth inhibition observed in pediatric and AYA OS models following exposure to BET + CHK1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

Pandya

Cheng

Saadatzadeh

et al. 2020

Cancers

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Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

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BRD4 facilitates DNA damage response and represses CBX5/Heterochromatin protein 1 (HP1)

Cited by 25 publications

References 31 publications

Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression

Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression

Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

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