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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 [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181406 | GEO | 2022/01/13

REPOSITORIES: GEO

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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

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

Project description: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

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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

2016-08-20 | GSE85840 | GEO

Bromodomain and extra-terminal (BET) inhibitors regulate NK cell biology by inhibiting BRD2 mediated NK cytolytic activity and BRD2/BRD4 mediated inflammatory function

Project description:Natural killer cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a combined chemico-genetic approach, we have identified that BET bromodomains BRD2 and BRD4 are central regulators of NK cell responses. We show that both BRD2 and BRD4 play a key regulatory function in controlling NK cell specific inflammatory responses. However, knockdown of BRD2 but not BRD4 impairs NK cell cytolytic response, highlighting a redundant role for BRD4 in regulating NK cell killing. We further show that the prototypic monovalent BET inhibitor impairs in vitro NK cell mediated killing of cancer target cells, while the bivalent BET bromodomain AZD5153 does not. We ascribe these differences to the preferential affinity of JQ1(+) to BRD2, while AZD5153 has a higher affinity for BRD4. Our work suggests that inhibiting BET bromodomains may be an effective therapeutic strategy for controlling inflammatory function. Given that BRD2 but not BRD4 inhibition can impair NK cell mediated killing, our findings also have clinical significance in light of the ongoing clinical application of BET bromodomains in oncology.

2021-03-16 | GSE156423 | GEO

Toggling of BRD4 functions is triggered through its phosphorylation by JNK

Project description:BRD4 is a key regulatory factor in multiple cancers and cellular stress responses with pleotropic functions. BRD4 regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities, respectively. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that in response to a broad range of stimuli, this switch is mediated by the JNK kinase which directly interacts with BRD4. JNK specifically phosphorylates human BRD4 at Ser1117, Thr1186 and Thr1212, triggering transient BRD4 release from chromatin. JNK phosphorylation of BRD4 halts its HAT-mediated chromatin regulation and activates its transcription-enhancing kinase function. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. BRD4 release from chromatin augments its interaction with and phosphorylation of key transcriptional regulators RNA Pol II, PTEFb and c-MYC. The PP4 phosphatase dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which promotes its interaction with RNA Pol II at transcriptionally active sites. Accordingly, JNK-mediated release of BRD4 from chromatin leads to significantly elevated transcription of BRD4-regulated immune and inflammatory response genes through enhanced BRD4-Pol II interaction at the promoters of these genes. JNK phosphorylation of BRD4 occurs during T-cell activation and is required for epithelial to mesenchymal transition (EMT) in prostate cancer cells. These findings thus characterize a novel mechanism that triggers the transition of BRD4 from a chromatin regulator to transcriptional activator during stress/immune/inflammatory responses and EMT.

2024-01-16 | MSV000093873 | MassIVE

BET inhibition targets ABC-DLBCL constitutive B-cell receptor signaling through PAX5

Project description:B-cell receptor (BCR) signaling is essential for the diffuse large B-cell lymphoma (DLBCL) subtype that originates from activated B-cells (ABC). ABC-DLBCL cells are sensitive to Bruton tyrosine kinase intervention. However, ABC-DLBCL patients had overall response rates of 33-37% for Bruton tyrosine kinase inhibitors, suggesting the evaluation of combination-based treatment for improved efficacy. We investigated the efficacy and mechanism of AZD5153 combined with the Bruton tyrosine kinase inhibitor acalabrutinib in ABC-DLBCL preclinical models. AZD5153 is a bivalent BET inhibitor that simultaneously engages the two bromodomains of BRD4. Adding AZD5153 to acalabrutinib demonstrated a combination benefit in ABC-DLBCL cell lines and PDX models. Differential expression analyses in treated tumors identified significant alterations of BCR, PAX5, RELB/alternative NFκB, and toll-like receptor/interferon signaling. PAX5 is a transcription factor for BCR signaling genes and may be critical to the perpetually active BCR signaling in ABC-DLBCL. We demonstrate that AZD5153 decreases PAX5 expression, while acalabrutinib disruption to BCR signaling inhibits PAX5 activation. Furthermore, several interferons were decreased by AZD5153 and acalabrutinib in tumors. Adding IFNß1 to cells in vitro restored PAX5 activation. Our results demonstrate AZD5153 enhances the efficacy of acalabrutinib through PAX5 and BCR mechanisms that are critical for ABC-DLBCL.

2022-08-24 | GSE211549 | GEO

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

Targeting super-enhancer induced gene expression using novel BRD4 inhibitor OTX015 in preclinical models of MYCN-amplified neuroblastoma

Project description:Bromodomain-containing protein 4 (BRD4) functions as an epigenetic reader and binds to so-called super-enhancer regions of driving oncogenes such as MYC in cancer. We investigated the possibility to target super-enhancer regulated genes in neuroblastoma and in MYCN amplified disease in particular. We used OTX015, the first small-molecule BRD4 inhibitor to enter clinical phase I/II trials in adults, to test the feasibility to specifically target super-enhancer regulated gene-expression in neuroblastoma. BRD4 inhibition lead to significant transcriptional down-regulation of genes that were associated with super-enhancers, supporting the notion that BRD4 preferentially acts at these chromatin sites. BRD4 inhibition not only attenuated MYCN transcription but most significantly affected MYCN-regulated transcriptional programs.

2016-07-03 | E-MTAB-3672 | biostudies-arrayexpress

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