Bromodomain-containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics.
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ABSTRACT:
SUBMITTER: Li L
PROVIDER: S-EPMC8486215 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As a class, 'BET' inhibitors disrupt binding of bromodomain and extra-terminal motif (BET) proteins, BRD2, BRD3, BRD4 and BRDT, to acetylated histones preventing recruitment of RNA polymerase 2 to enhancers and promoters, especially super-enhancers, to inhibit gene transcription. As such, BET inhibitors may be useful therapeutics for treatment of cancer and inflammatory disease. For example, the small molecule BET inhibitor, JQ1, selectively represses MYC, an important oncogene regulated by a super-enhancer. IFN-?, a critical cytokine for both innate and adaptive immune responses, is also regulated by a super-enhancer. Here, we show that JQ1 represses IFN-? expression in TH1 polarized PBMC cultures, CD4+ memory T cells, and NK cells. JQ1 treatment does not reduce activating chromatin marks at the IFNG locus, but displaces RNA polymerase II from the locus. Further, IFN-? expression recovers in polarized TH1 cultures following removal of JQ1. Our results show that JQ1 abrogates IFN-? expression, but repression is reversible. Thus, BET inhibitors may disrupt the normal functions of the innate and adaptive immune response.
| S-EPMC6635431 | biostudies-literature
Project description:Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20-40 years) and are classified as seminoma or non-seminoma. TGCTs are commonly treated by orchiectomy and chemo- or radiotherapy. However, a subset of metastatic non-seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumour therapy, which interferes with the function of 'bromodomain and extraterminal (BET)' proteins. JQ1-treated TGCT cell lines display up-regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down-regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma-like TCam-2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.
| S-EPMC5487916 | biostudies-literature
Project description:Angiogenesis dysregulation contributes to inflammation, infections, immune disorders, and carcinogenesis. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that recognizes histone proteins and acts as a transcriptional regulator to trigger tumor growth and the inflammatory response. The pan-bromodomain and extra-terminal domain (BET) inhibitor, (+)-JQ1 (1), was reported to inhibit angiogenesis. However, owing to the non-selectivity action of (+)-JQ1 towards all BET family members, the role of BRD4 and that of its bromodomains (BD1 and BD2) in angiogenesis remains elusive. Herein, we identified a potent BRD4 inhibitor, ZL0513 (7), which exhibited significant anti-angiogenic effects in chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. This inhibitor also directly suppressed the viability and tube formation of human umbilical vascular endothelial cells (HUVECs). Moreover, ZL0513 (7) was found to inhibit the phosphorylation of c-jun and c-fos, important members of activating protein-1 (AP-1) transcription factor complexes that enhance angiogenesis. The findings on this novel BRD4 inhibitor indicate that, in addition to being a powerful pharmacological tool for further elucidating the roles and functions of BRD4 and its BD domains in angiogenesis, it may serve as a potential therapeutic strategy for targeting the vasculature in various angiogenesis-dysregulated human diseases.
| S-EPMC7381267 | biostudies-literature
Project description:Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. In this study, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs, as indicated by defective upregulation of costimulatory molecules and CD83, as well as reduced secretion of IL-12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83, and IL-12. The activation of STAT5 in Mo-DCs is mediated by GM-CSF produced following LPS stimulation. Activated STAT5 then leads to increased expression of both GM-CSF and GM-CSFR, triggering an autocrine loop that further enhances STAT5 signaling and enabling Mo-DCs to acquire a more mature phenotype. JQ1 decreases the ability of Mo-DCs to induce allogeneic CD4(+) and CD8(+) T cell proliferation and production of proinflammatory cytokines. Furthermore, JQ1 leads to a reduced generation of inflammatory CD8(+) T cells and decreased Th1 differentiation. Thus, JQ1 impairs LPS-induced Mo-DC maturation by inhibiting STAT5 activity, thereby generating cells that can only weakly stimulate an adaptive-immune response. Therefore, JQ1 could have beneficial effects in treating T cell-mediated inflammatory diseases.
| S-EPMC4369449 | biostudies-literature
Project description:Corticotrophinomas represent 10% of all surgically removed pituitary adenomas, however, current treatment options are often not effective, and there is a need for improved pharmacological treatments. Recently, JQ1+, a bromodomain inhibitor that promotes gene transcription by binding acetylated histone residues and recruiting transcriptional machinery, has been shown to reduce proliferation in a murine corticotroph cell line, AtT20. RNA-Seq analysis of AtT20 cells following treatment with JQ1+ identified the calcium-sensing receptor (CaSR) gene as significantly downregulated, which was subsequently confirmed using real-time PCR and Western blot analysis. CaSR is a G protein-coupled receptor that plays a central role in calcium homeostasis but can elicit non-calcitropic effects in multiple tissues, including the anterior pituitary where it helps regulate hormone secretion. However, in AtT20 cells, CaSR activates a tumour-specific cAMP pathway that promotes ACTH and PTHrP hypersecretion. We hypothesised that the Casr promoter may harbour binding sites for BET proteins, and using chromatin immunoprecipitation (ChIP)-sequencing demonstrated that the BET protein Brd3 binds to the promoter of the Casr gene. Assessment of CaSR signalling showed that JQ1+ significantly reduced Ca2+e-mediated increases in intracellular calcium (Ca2+i) mobilisation and cAMP signalling. However, the CaSR-negative allosteric modulator, NPS-2143, was unable to reduce AtT20 cell proliferation, indicating that reducing CaSR expression rather than activity is likely required to reduce pituitary cell proliferation. Thus, these studies demonstrate that reducing CaSR expression may be a viable option in the treatment of pituitary tumours. Moreover, current strategies to reduce CaSR activity, rather than protein expression for cancer treatments, may be ineffective.
| S-EPMC8345903 | biostudies-literature
Project description:The bromodomain and extra-terminal domain inhibitor JQ1 has marked antitumor activity against several hematologic malignancies as well as solid tumor models. Here, we investigated its activity in vitro and in vivo against models of childhood rhabdomyosarcoma and Ewing sarcoma. In vitro, JQ1 (but not the inactive enantiomer JQ1R) inhibited cell proliferation and increased G1 fraction of cells, although there was no correlation between cell line sensitivity and suppression of c-MYC or MYCN. In vivo, xenografts showed significant inhibition of growth during the period of treatment, and rapid regrowth after treatment was stopped, activity typical of antiangiogenic agents. Furthermore, xenografts derived from cell lines intrinsically resistant or sensitive to JQ1 in vitro had similar sensitivity in vivo as xenografts. Further investigation showed that JQ1 reduced tumor vascularization. This was secondary to both drug-induced downregulation of tumor-derived growth factors and direct effects of JQ1 on vascular elements. JQ1 suppressed VEGF-stimulated vascularization of Matrigel plugs in mice, and in vitro suppressed differentiation, proliferation, and invasion of human umbilical cord vascular endothelial cells (HUVEC). In HUVECs, JQ1 partially suppressed c-MYC levels, but dramatically reduced AP-1 levels and activity through suppression of the AP-1-associated protein FOSL1. Our data suggest that the antitumor activity of JQ1 in these sarcoma models is largely a consequence of its antiangiogenic activity. Mol Cancer Ther; 15(5); 1018-28. ©2016 AACR.
| S-EPMC4873398 | biostudies-literature
Project description:Bromodomain and extraterminal domain proteins, especially bromodomain‑containing protein 4 (Brd4), have recently emerged as therapeutic targets for several cancers, although the role and mechanism of Brd4 in glioblastoma multiforme (GBM) are unclear. In this study, we aimed to explore the underlying mechanisms of the anti‑tumor effects of Brd4 and the bromodomain inhibitor JQ1 on glioma stem cells (GSCs). In vitro, JQ1 and small interfering RNAs targeting Brd4 (siBrd4) inhibited the proliferation and self‑renewal of GSCs. In vivo, JQ1 significantly inhibited the growth of xenograft GSCs tumors. The RNA‑seq analysis revealed that the PI3K‑AKT pathway played an important role in GBM. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 phosphorylation was downregulated by exposure to JQ1 in GSCs, thereby reducing PI3K and AKT activity. In addition, treatment with JQ1 inhibited MMP expression, thereby inhibiting degradation of the extracellular matrix by MMP and angiogenesis in GBM tumors. Suppression of AKT phosphorylation inhibited the expression of the retinoblastoma/E2F1 complex, resulting in cell cycle arrest. In addition, treatment with siBrd4 or JQ1 induced apoptosis by activating AKT downstream target genes involved in apoptosis. In conclusion, these results suggest that Brd4 has great potential as a therapeutic target, and JQ1 has notable anti‑tumor effects against GBM which may be mediated via the VEGF/PI3K/AKT signaling pathway.
| S-EPMC6741838 | biostudies-other
Project description:Background and purposeTh17 cells play critical roles in chronic inflammation, including fibrosis. Histone acetyltransferase p300, a bromodomain-containing protein, acetylates RORγt and promotes Th17 cell development. The bromodomain inhibitor JQ1 was shown to alleviate Th17-mediated pathologies, but the underlying mechanism remains unclear. We hypothesized that JQ1 suppresses the response of Th17 cells by impairing p300-mediated acetylation of RORγt.Experimental approachThe effect of JQ1 on p300-mediated acetylation of RORγt was investigated in HEK293T (overexpressing Flag-p300 and Myc-RORγt) and human Th17 cells through immunoprecipitation and western blotting. To determine the regions of p300 responsible for JQ1-mediated suppression of HAT activity, we performed HAT assays on recombinant p300 fragments with/without the bromodomain, after exposure to JQ1. Additionally, the effect of JQ1 on p300-mediated acetylation of RORγt and Th17 cell function was verified in vivo, using murine Schistosoma-induced fibrosis models. Liver injury was assessed by histopathological examination and measurement of serum enzyme levels. Expression of Th17 effectors was detected by qRT-PCR, whereas IL-17- and RORγt-positive granuloma cells were detected by FACS.Key resultsJQ1 impaired p300-mediated RORγt acetylation in human Th17 and HEK293T cells. JQ1 failed to suppress the acetyltransferase activity of p300 fragments lacking the bromodomain. JQ1 treatment attenuated Schistosoma-induced fibrosis in mice, by inhibiting RORγt acetylation and IL-17 expression.Conclusions and implicationsJQ1 impairs p300-mediated RORγt acetylation, thus reducing the expression of RORγt target genes, including Th17-specific cytokines. JQ1-mediated inhibition of p300 acetylase activity requires the p300 bromodomain. Strategies targeting p300 may provide new therapeutic approaches for controlling Th17-related diseases.
| S-EPMC7280011 | biostudies-literature
Project description:PurposeNew therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer.Experimental designWe treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression.ResultsJQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation.ConclusionsThese preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430-40. ©2016 AACR.
| S-EPMC5241246 | biostudies-literature
Project description:Adenovirus-based vectors are among the most commonly used platforms for gene delivery and gene therapy studies. One of the obstacles for potential application is dose-related toxicity. We show here that adenovirus infection and Ad-mediated gene delivery can be enhanced by inhibitors of bromodomain and extra-terminal (BET) family proteins. We showed that JQ1, but not its inactive enantiomer (-)-JQ1, dose-dependently promoted Ad infection and Ad-mediated gene delivery in both epithelial and lymphocyte cells. Given orally, JQ1 also enhanced transgene expression in a murine tumor model. Inhibitors of histone deacetylases (HDACi) are among the commonly reported small molecule compounds which enhance Ad-mediated gene delivery. We found that JQ1 treatment did not cause histone acetylation nor expression of Ad attachment receptor CAR. Instead, JQ1 treatment induced an increase in BRD4 association with CDK9, a subunit of P-TEFb of transcription elongation. Concurrently, we showed that CDK9 inhibition blocked Ad infection and JQ1 enhancement on the infection. The study exemplifies the potentials of BET inhibitors like JQ1 in oncolytic virotherapy.
| S-EPMC6070498 | biostudies-literature