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Transcriptional changes induced by Brd4 inhibitor, AZD5153, in cancer cell lines

ABSTRACT: We sequenced mRNA from 12 human cancer cell lines treated with DMSO or AZD5153 for 24h to determine compound mechanism of action

ORGANISM(S): Homo sapiens

PROVIDER: GSE85840 | GEO | 2016/08/20

SECONDARY ACCESSION(S): PRJNA339566

REPOSITORIES: GEO

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Transcriptional changes induced by Brd4 inhibitor, AZD5153, in cancer cell lines

Project description:We sequenced mRNA from 12 human cancer cell lines treated with DMSO or AZD5153 for 24h to determine compound mechanism of action Measured mRNA levels in cell lines treated with either AZD5153 or DMSO for 24h

2016-08-20 | E-GEOD-85840 | biostudies-arrayexpress

AZD5153, a bivalent BRD4 inhibitor, inhibits hepatocellular cancer growth by modulating the HCC transcriptome through repression of critical oncogenes through dissociation of BRD4 from the enhancer/promoter regions of critical genes

Project description:Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death worldwide because of late stage detection when curative therapy is not available. The bromodomain and extraterminal (BET) protein BRD4 activates gene expression by interacting with histone H3K27-acetylated (H3K27Ac) chromatin. AZD5153 is an orally bioavailable, potent, bivalent BRD4 inhibitor, currently undergoing clinical trials in lymphoma and ovarian cancer patients. Here, we studied therapeutic potential of AZD5153 against HCC and elucidated the underlying mechanism. In conclusion, our results in preclinical models indicate that the combined effect of AZD5153 could be a novel targeted therapy for HCC and provides rationale for clinical trials of an AZD5153-FK866 combination as an effective and attractive strategy to treat this deadly disease.

2022-01-13 | GSE172186 | GEO

2022-01-13 | GSE181406 | GEO

AZD5153, a Bivalent BRD4 Inhibitor, Suppresses Hepatocarcinogenesis by Altering BRD4 Chromosomal Landscape and Modulating the Transcriptome of HCC Cells.

Project description:BRD4, a chromatin modifier frequently upregulated in a variety of neoplasms including hepatocellular cancer (HCC), promotes cancer cell growth by activating oncogenes through its interaction with acetylated histone tails of nucleosomes. Here, we determined the anti-HCC efficacy of AZD5153, a potent bivalent BRD4 inhibitor, and elucidated its underlying molecular mechanism of action. AZD5153 treatment inhibited HCC cell proliferation, clonogenic survival and induced apoptosis in HCC cells. In vivo, AZD5153-formulated lipid nanoemulsions inhibited both orthotopic and subcutaneous HCCLM3 xenograft growth in NSG mice. Mapping of BRD4- chromosomal targets by ChIP-seq analysis identified the occupancy of BRD4 with the promoters, gene bodies, and super-enhancers of both mRNA and noncoding RNA genes, which were disrupted upon AZD5153 treatment. RNA-seq analysis of polyadenylated RNAs showed several BRD4 target genes involved in DNA replication, cell proliferation, and anti-apoptosis were repressed in AZD5153-treated HCC cells. In addition to known tumor-promoting genes, e.g., c-MYC, YAP1, RAD51B, TRIB3, SLC17A9, JADE1, we found that NAPRT, encoding a key enzyme for NAD+ biosynthesis from nicotinic acid, was also suppressed in HCC cells by the BRD4 inhibitor. Interestingly, AZD5153 treatment upregulated NAMPT, whose product is the rate-limiting enzyme for NAD+ synthesis from nicotinamide. This may explain why AZD5153 acted in concert with FK866, a potent NAMPT inhibitor, in reducing HCC cell proliferation and clonogenic survival. In conclusion, our results identified novel targets of BRD4 in the HCCLM3 cell genome and demonstrated anti-HCC efficacy of AZD5153, which was potentiated in combination with an NAMPT inhibitor.

| S-EPMC8987780 | biostudies-literature

Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor.

Project description:In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both q.d. and b.i.d. dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses. The model was then extended to incorporate preexisting myelosuppression where bone marrow function is inhibited by acute myeloid leukemia. Under these conditions, duration of platelet count recovery has the potential to be prolonged due to drug-induced myelosuppression.

| S-EPMC5488126 | biostudies-literature

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages.

Project description:High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However, in HGSOC, the impact of the therapies aiming at these targets remains unsatisfying. Tumor-associated macrophages (TAMs) in HGSOC make up a large part of the TMEs and transform between diverse phenotypes under different treatments. AZD5153 inhibiting BRD4, as a potential therapeutic strategy for HGSOC, was demonstrated to confer controversial plasticity on TAMs, which shows the need to uncover its impact on TAMs in HGSOC. Therefore, we established models for TAMs and TAMs co-culturing with T lymphocytes in vitro. Via RT-PCR and flow cytometry, we find that AZD5153 resets TAMs from M2-type macrophages to M1-like macrophages, consequently promoting pro-inflammatory cytokine secretion and thus activating CD8+ cytotoxic T lymphocytes (CTLs) in vitro. This modification occurs on MAF transcripts in TAMs and modified by BRD4, which is the target of AZD5153. Importantly, the 3-D microfluid model demonstrates that AZD5153 sensitizes ovarian cancer to anti-PD-L1 therapy. Our results clarify that besides eliminating tumor cells directly, AZD5153 works as a regulator of the TAM phenotype, providing a novel strategy combining AZD5153 and PD-1/PD-L1 antibody that could benefit HGSOC patients.

| S-EPMC7058627 | biostudies-literature

KDM5C-mediated BRD4 recruitment is essential for active states of enhancers and BET inhibitor sensitivity [RNA-seq]

Project description:To investigate the effect of the KDM5C depletion on transcription, we established HeLa cell lines in which KDM5C has been knocked off. To explore the effect of synergistic lethal action of KDM5C PROTAC drug and BETi on transcription, we treated HeLa cells with JQ1, or compound 3b, or in combination.

2024-01-17 | GSE236168 | GEO

A novel LSD1 inhibitor T-3775440 induces transdifferentiation in AML cell lines

Project description:We describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) are highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation-like phenotypic change from erythroid/megakaryocytic lineages into granulomonocytic lineage. Our findings provide the rationale for testing LSD1 inhibitors as potential treatments with a novel mechanism of action for AML, particularly AEL and AMKL.

2017-01-01 | GSE87580 | GEO

BRD4 Chromatin immunoprecipitation and Sequencing

Project description:We report BET bromodomain inhibitors (BETi) as regulators of keratinocyte stem cell fate. BETi displace BET proteins, including BRD4 from chromatin, inducing acute transcriptional changes at selected target genes. To gain insight into the compound mechanism of action, we assayed BRD4 chromatin occupancy genome-wide in keratinocytes subjected to BETi treatment. Specifically, BRD4 chromatin binding was analyzed following two treatments [125nM (low) versus 1250nM (high)] and three time points (30min, 6h and 6h treatment followed by compound removal for 3h (6m3h)).

2020-10-15 | GSE130365 | GEO

Transcriptomic analysis of Human Umbilical Vein Endothelial Cells (HUVEC) in response to compound treatment

Project description:Human Umbilical Vein Endothelial Cells were treated with three newly synthesized compounds and DMSO as vehicle. Total RNA was isolated 6 and 24h after treatment and gene expression analysis was performed. Three independent experiments were performed, corresponding to rep1, rep2 and rep3. Experiment 1 (rep1) contained all substances at both time points tested. Experiment 2 (rep2) contained two of the compounds and control DMSO at both time points. Experiment 3 (rep3) contained the third compound and control DMSO at both time points.

2016-06-30 | GSE75588 | GEO

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