BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells

Wroblewski, Mark; Scheller, Marina; Udonta, Florian; Bauer, Raimund; Schlichting, Jara; Zhao, Lina; Ben-Batalla, Isabel; Gensch, Victoria; Päsler, Sarina; Wu, Lei; Wanior, Marek; Taipaleenmäki, Hanna; Bolamperti, Simona; Najafova, Zeynab; Pantel, Klaus; Bokemeyer, Carsten; Qi, Jun; Hesse, Eric; Knapp, S.; Johnsen, Steven A.; Loges, Sonja

doi:10.3324/haematol.2017.181354

Cited by 26 publications

(28 citation statements)

References 34 publications

(38 reference statements)

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“…Taking into consideration the importance of BRD4 in malignant diseases, JQ1, a BRD2 and BRD4 dual inhibitor, has been designed, which competitively occupies the BRD4 pocket structure by binding to acetylated lysine and subsequently deploy transcription protein complexes and RNA polymerase, which inhibits the transcription of numerous genes. Furthermore, JQ1 exhibits inhibitory activity against several cancer cell lines including those derived from CRC 22, 23. However, dual targeting of BRD2 and BRD4 have presented some limitations, recent studies revealed their opposing biological effects in some cancer types, which BRD2 inhibition increased cancer cell invasiveness.…”

Section: Introductionmentioning

confidence: 99%

BRD4 Inhibitor AZD5153 Suppresses the Proliferation of Colorectal Cancer Cells and Sensitizes the Anticancer Effect of PARP Inhibitor

Zhang¹,

Li²,

Xiao³

et al. 2019

Int. J. Biol. Sci.

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Background: Bromodomain-containing protein 4(BRD4) is reported to play a vital role in the development of numerous malignant diseases, which is considered as a promising target for cancer therapy. AZD5153, a novel specific BRD4 inhibitor, showed potent anticancer effects in several cancer types, but its therapeutic potential has not been fully evaluated in colorectal cancer cells.Objective: We sought to evaluate the therapeutic potential of BRD4 inhibition of by AZD5153 and its combined anticancer cancer effect with PARP inhibitor BMN673 in vitro and in vivo in colorectal cancer.Methods: We analyzed The Cancer Genome Atlas (TCGA) database to investigate BRD4 expression in colorectal cancer patient. Clonogenic assays 、MTT assays and PI/Annexin V staining were used to determine the effect of AZD5153 and BMN673 and combination therapy on cell viability and apoptosis induction. Western blotting was applied to detect relevant molecules changes. Propidium iodide staining was performed to examine cell cycle distributions after monotherapy or combination therapy. Nude mice xenograft model was generated to confirm the therapeutic effect of AZD5153 and BMN673 combination in vivo, and IHC staining was used to detect the expression level of BRD4 and related markers in colorectal patient and xenograft.Results: Analysis of TCGA database indicated that BRD4 was overexpressed in colorectal cancer patient. The clonogenic and MTT assays and PI/Annexin V staining demonstrated that AZD5153 significantly suppressed cell proliferation and induced apoptosis in colorectal cancer cells HCT116 and LoVo. Western blotting showed that AZD5153 inhibited the expression of c-Myc and increased expression of the apoptosis markers, cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), besides, we found that BRD4 knockdown could also inhibited cell proliferation and induced cell apoptosis. Moreover, AZD5153 inhibited the expression of Wee1 and impaired G2M cell cycle checkpoint, thus sensitized the anticancer effect of BMN673 in vitro and in vivo.Conclusion: Our data revealed that AZD5153suppressed the proliferation of colorectal cancer cells and sensitized them to the anticancer effect of the PARP inhibitor BMN673 via Wee1 inhibition in vitro and in vivo. This suggested that targeting BRD4 might be a valuable strategy for colorectal cancer treatment.

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Section: Introductionmentioning

confidence: 99%

BRD4 Inhibitor AZD5153 Suppresses the Proliferation of Colorectal Cancer Cells and Sensitizes the Anticancer Effect of PARP Inhibitor

Zhang¹,

Li²,

Xiao³

et al. 2019

Int. J. Biol. Sci.

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“…In recent decades, large breakthroughs have led to functional evaluation, epigenetic profiling and targeted therapy in human cancer . Cancer cells characteristically exhibit aberrant epigenetic regulation and use the regulatory components of the chromatin to carry out transcriptional programmes initiating oncogenesis . There are two particularly important epigenetic readers, bromodomain and extraterminal domain (BET) proteins, that have two characteristic tandem bromodomains (BD1 and BD2) and primarily recognize the acetylated lysine of histones H3 and H4, and occasionally acetylated nonhistone proteins, to modulate gene expression .…”

Section: Introductionmentioning

confidence: 99%

“…11 Cancer cells characteristically exhibit aberrant epigenetic regulation and use the regulatory components of the chromatin to carry out transcriptional programmes initiating oncogenesis. 12,13 There are two particularly important epigenetic readers, bromodomain and extraterminal domain (BET) proteins, that have two characteristic tandem bromodomains (BD1 and BD2) and primarily recognize the acetylated lysine of histones H3 and H4, and occasionally acetylated nonhistone proteins, to modulate gene expression. 11,14,15 A well-studied BET family member, BRD4, usually recruits the P-TEFb transcription elongation factor or other transcriptional factors or chooses modifiers of histones to promote activation of target genes at the transcriptional stage.…”

mentioning

confidence: 99%

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

Sun²,

et al. 2020

J Cellular Molecular Medi

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In gastrointestinal stromal tumours (GISTs), the function of bromodomain‐containing 4 (BRD4) remains underexplored. BRD4 mRNA abundance was quantified in GISTs. In the current study, we investigated the role of BRD4 in GISTs. Our results show a significant enhancement in BRD4 mRNA and a shift from very low‐risk/low‐risk to high‐risk levels as per NCCN specifications. Overexpression of BRD4 correlated with unfavourable genotype, nongastric location, enhanced risk and decreased disease‐free survival, which were predicted independently. Knockout of BRD4 in vitro suppressed KIT expression, which led to inactivation of the KIT/PI3K/AKT/mTOR pathway, impeded migration and cell growth and made the resistant GIST cells sensitive to imatinib. The expression of KIT was repressed by a BRD4 inhibitor JQ1, which also induced myristoylated‐AKT‐suppressible caspases 3 and 9 activities, induced LC3‐II, exhibited dose‐dependent therapeutic synergy with imatinib and attenuated the activation of the PI3K/AKT/mTOR pathway. In comparison with their single therapy, the combination of JQ1/imatinib more efficiently suppressed the growth of xenografts and exhibited a reduction in KIT phosphorylation, a decrease in Ki‐67 and in the levels of phosphorylated PI3K/AKT/mTOR and enhanced TUNEL staining. Thus, we characterized the biological, prognostic and therapeutic implications of overexpressed BRD4 in GIST and observed that JQ1 suppresses KIT transactivation and nullifies the activation of PI3K/AKT/mTOR, providing a potential strategy for treating imatinib‐resistant GIST through dual blockade of KIT and BRD4.

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“…In mice, JQ1 treatment affects the expression of synaptic proteins and receptors in neurons with functional effects on long-term memory and decreased seizure susceptibility (Korb et al 2015). Murine JQ1 treatment is also associated with reductions in spleen and thymus weights (Wroblewski et al 2018) as well as sperm count and motility (Matzuk et al 2012). In an inducible transgenic RNA interference mouse model, systemic BRD4 suppression in adult animals was associated with toxicity in several organs including altered hematopoiesis, follicular dysplasia, and decreased cellular diversity along with stem cell depletion in the small intestine (Bolden et al 2014).…”

Section: Bet Bromodomains Attenuate Pathological Cardiac Remodellingmentioning

confidence: 99%

Drugging transcription in heart failure

Padmanabhan

Haldar

2019

The Journal of Physiology

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Pathological Stress Improved Function Present Future THERAPY ERK Pathogenic Gene mRNA Cytoplasm Nucleus JQ1 ExtracellularAbstract Advances in our understanding of the basic biology and biochemistry of chromatin structure and function at genome scales has led to tremendous growth in the fields of epigenomics and transcriptional biology. While it has long been appreciated that transcriptional pathways are dysregulated in failing hearts, only recently has the idea of disrupting altered transcription by Arun Padmanabhan is a physician-scientist at the University of California, San Francisco and a postdoctoral scholar at the Gladstone Institutes. His research focuses on understanding the gene-regulatory and epigenetic pathways that govern cell fate decisions during early cardiac development and cell state transitions in the pathophysiology of heart failure. Saptarsi Haldar is a physician-scientist who is currently Vice President of Research at Amgen where he heads Cardiovascular and Metabolic Discovery, based in South San Francisco. He is also a Professor of Medicine at the University of California, San Francisco (visiting clinical appointment) and a Visiting Investigator at the Gladstone Institutes. His academic laboratories' research focuses on gene regulatory signalling mechanisms that govern cardiovascular and metabolic homeostasis. Abstract figure legendStress-or injury-induced cardiac signalling cascades converge on the nucleus to trigger global shifts in gene expression that contribute to the cycle of adverse remodelling and impaired function of the heart. Current pharmacological therapies target a very proximal step in stress-dependent cardiac signalling (e.g. antagonists of the β1 adrenergic receptor). As transcription factors and the chromatin regulatory apparatus act as the terminal signal integrators that transduce these signals into changes in cell identity, disrupting altered transcription by targeting chromatin-associated proteins has emerged as an exciting potential therapeutic avenue.

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BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells

Cited by 26 publications

References 34 publications

BRD4 Inhibitor AZD5153 Suppresses the Proliferation of Colorectal Cancer Cells and Sensitizes the Anticancer Effect of PARP Inhibitor

BRD4 Inhibitor AZD5153 Suppresses the Proliferation of Colorectal Cancer Cells and Sensitizes the Anticancer Effect of PARP Inhibitor

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

Drugging transcription in heart failure

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