Search Results (121)

The dynamic crosstalk between the tumor microenvironment (TME) and triple negative breast cancer (TNBC) cells plays a critical role in tumor progression and treatment resistance. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signaling in BC, where its overexpression modulates oncogenic pathways contributing to invasion and metastasis. Epigenetic dysregulation by Bromodomain and Extra-Terminal domain (BET) proteins critically influences key oncogenic pathways and cytokine expression in TNBC. Given that the BET-inhibitor JQ1 blocks TNBC cell growth, in this study we investigated its potential regulatory effects on the IL-20RA pathway. IL-20RA was found expressed across multiple BC cell lines compared to non-tumorigenic cells, with the highest levels detected in MDA-MB-231 and MDA-MB-468 cells. In both cell lines, JQ1 treatment significantly downregulated IL-20RA expression at gene and protein levels, accompanied by a reduction in the oncogenic JAK/STAT signaling pathway, and programmed death-ligand 1 (PD-L1) expression. Parallel in vivo experiments using TNBC xenograft models confirmed these findings, showing reduced IL-20RA and PD-L1 expression alongside decreased phosphorylation of JAK and STAT3. Overall, this study uncovers a novel interplay between BET inhibition and the IL-20RA/STAT3 axis, suggesting JQ1 as a valid therapeutic option for TNBC characterized by high IL-20RA expression. Full article

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition, and epigenetic or metabolic targets including histone deacetylases (HDACs), bromodomain and extra-terminal proteins (BET), and mutant isocitrate dehydrogenases (IDH1/2). Across these areas, we summarize recurrent resistance mechanisms and the rationale for combination or sequential approaches. Biologic targeted therapy is discussed in parallel, including immune checkpoint blockade, antibody–drug conjugates, bispecific antibodies (BsAb), and cell therapies such as chimeric antigen receptor T cells, with emphasis on biomarker-guided patient stratification. Finally, we outline emerging directions beyond canonical nodes, including modulation of the p53-MDM2/MDM4 axis, ferroptosis control through AIFM2/FSP1, and innate immune pathways such as CD47-SIRPa and the stimulator of interferon genes (STING). Overall, the field is shifting from single-target inhibition toward integrated strategies that combine precise molecular targeting with an understanding of signaling network dynamics, resistance evolution, and therapeutic vulnerabilities. Full article

Epigenetic dysregulation is increasingly recognized as a key driver of glioblastoma (GBM), with bromodomain-containing protein 4 (BRD4) emerging as a critical regulator of tumor malignancy. GBM is an aggressive brain tumor marked by diffuse infiltration, a population of stem-like cells and multiple resistance mechanisms, which together render it largely incurable. Standard treatment, consisting of surgical resection followed by radiotherapy and temozolomide chemotherapy, confers only limited therapeutic benefit, while a member of the bromodomain and extra-terminal (BET) family, BRD4, regulates transcriptional programs essential for oncogene activation, chromatin stability and glioma cell survival. Its expression is markedly elevated in GBM relative to normal brain tissue, implicating BRD4 in tumor initiation, progression and therapeutic resistance. Recent advances have enabled the development of selective BRD4 inhibitors and degraders capable of penetrating the blood–brain barrier and preferentially targeting glioma cells. Preclinical and early-phase clinical studies indicate that these agents suppress tumor growth and may enhance the efficacy of existing treatments. Although BRD4 clearly influences glioma progression and modulates key oncogenic pathways, the precise mechanisms underlying BRD4-driven gliomagenesis remain only partially understood. Ongoing research continues to advance knowledge of its multifaceted functions. This review summarizes current knowledge on BRD4 in GBM, evaluates emerging BRD4-targeted therapeutic strategies and outlines major challenges and future directions for clinical translation. Full article

NUT carcinoma (NC) is a rare exceptionally aggressive malignancy, defined by NUTM1 gene translocations, most commonly generating a BRD4::NUTM1 fusion that results in a poor prognosis and limited therapeutic options. Oncolytic virotherapy has emerged as a promising strategy for NC, and the dual bromodomain and extra-terminal domain (BET) and p300/CBP inhibitor NEO2734 has demonstrated potent antiproliferative activity. To investigate multimodal therapeutic approaches that combine epigenetic modulation with immunogenic and cytotoxic effects of oncolytic viruses (OVs), we evaluated two recombinant OVs, including the herpes simplex virus talimogene laherparepvec (T-VEC) and a measles vaccine virus (MeV-GFP), in combination with NEO2734 in four distinct NC cell lines. Viability assays revealed enhanced tumor cell reduction with all combinations, including synergistic effects with T-VEC combinations. Cell cycle analysis showed G1 arrest with NEO2734 alone, whereas its combination with T-VEC resulted in S-phase broadening and reduced G2-phase populations, consistent with replicative stress and increased cytotoxicity. Evaluation of immunogenic cell death (ICD) markers displayed elevated ATP and HMGB1 levels and increased surface calreticulin with T-VEC and NEO2734 combinations. Overall, these findings indicate that combining OVs with BET/p300 inhibitors elicits potent antitumor responses, supports synergistic interactions and immunogenicity, and warrants further investigation in multimodal therapeutic strategies for NC. Full article

Background/Objectives: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders. Despite its multifactorial etiology, PD pathophysiology shared specific features such as cytoplasmic α-synuclein inclusions, oxidative stress, mitochondrial dysfunction, and impaired autophagy. Bromodomain and Extra-Terminal domain (BET) proteins, functioning as epigenetic readers, have recently emerged as promising therapeutic targets due to their regulatory role in redox homeostasis, neuroinflammation, and autophagy. However, their potential involvement in PD pathophysiology remains largely unexplored. Therefore, we aimed at evaluating whether BET modulation could ameliorate the parkinsonian phenotype in two cellular models. Methods: Differentiated SH-SY5Y and N1E-115 neuronal cells were exposed to rotenone toxin to mimic PD phenotype and co-treated with the small BET inhibitor JQ1. Results: BET inhibition significantly counteracted rotenone-induced cell death, neuromorphological alterations, and α-synuclein accumulation. These protective effects were accompanied by restoration of redox balance, as indicated by enhanced activation of the antioxidant system and suppression of the pro-oxidant NADPH oxidase complex. Moreover, JQ1 treatment alleviated mitochondrial dysfunction and corrected autophagy impairments triggered by rotenone. Conclusions: These data highlight a novel role for BET proteins in neurodegeneration, suggesting that their modulation may represent a promising approach to counteract PD neuropathology. Full article

Uterine Fibroids (UFs) are the most common benign tumors in women of reproductive age, affecting ~77% of women overall and are clinically manifest in ~25% by age 50. Bromodomain and extra-terminal domain (BET) proteins play key roles in epigenetic transcriptional regulation, influencing many biological processes, such as proliferation, differentiation, and DNA damage response. Although BET dysregulation contributes to various diseases, their specific role in the pathogenesis of UFs remains largely unexplored. The present study aimed to determine the expression pattern of BET proteins in UFs and matched myometrium and further assess the impact of BET inhibitors on UF phenotype and epigenetic changes. Our studies demonstrated that the levels of Bromodomain-containing protein (BRD)2 and detection rate of BRD4 were significantly altered in UFs compared to matched myometrium, suggesting that aberrant BET protein expression may contribute to the pathogenesis of UFs. To investigate the biological effects of BET proteins, two small-molecule inhibitors, JQ1 and I-BET762, were used to assess their impact on UF cell behavior and transcriptomic profiles. Targeted inhibition of BET proteins markedly reduced UF cell viability compared with myometrial cells and induced cell cycle arrest. Unbiased transcriptomic profiling coupled with bioinformatic analysis revealed that BET inhibition altered multiple biological pathways, including G2M checkpoint, E2F targets, mitotic spindle, mTORC1 signaling, TNF-α signaling via NF-κB, and inflammatory response, as well as reprogrammed the UF cell epigenome. Notably, BET inhibition decreased the expression of several genes encoding extracellular matrix (ECM) proteins, a hallmark of UFs. Collectively, these results support that BET proteins play a pivotal role in regulating key signaling pathways and cellular processes in UFs. Targeting BET proteins may therefore represent a promising non-hormonal therapeutic strategy for UF treatment. Full article

Bromodomain and extraterminal domain (BET) proteins act as epigenetic regulators of gene transcription. BET inhibitors have shown therapeutic potential in various models of heart failure; however, their efficacy in atrial fibrillation (AF) remains incompletely understood. This study investigated the effects of the BET inhibitor JQ1 in a mice model of AF. Wild-type male C57BL/6 mice were randomized into four groups: control, JQ1 alone (50 mg/kg, intraperitoneal), angiotensin II (AngII; 1 μg/kg/min), and AngII plus JQ1. After 2 weeks, electrophysiological studies revealed that JQ1 significantly reduced AngII-induced AF inducibility and duration. It also attenuated left atrial enlargement, diastolic dysfunction, and cardiac fibrosis. Molecular analyses indicated that JQ1 suppressed the AngII-induced upregulation of pro-fibrotic genes and restored Sirt1 expression. Moreover, JQ1 also inhibited AngII-enhanced oxidized CaMKII and phosphorylated RyR2 levels. In HL-1 atrial cardiomyocytes, JQ1 improved calcium handling abnormalities, shortened prolonged action potential duration (APD), and restored mitochondrial respiration and adenosine triphosphate (ATP) production, all of which had been impaired by AngII. These findings suggest that BET inhibition by JQ1 mitigates structural and electrical remodeling associated with AF by attenuating atrial fibrosis, and by restoring calcium homeostasis, mitochondrial function, and Sirt1 expression. JQ1 may represent a novel therapeutic strategy for the prevention and treatment of AF. Full article

Bromodomain and extraterminal domain (BET) family proteins are ubiquitous transcriptional co-activators that function broadly in cellular differentiation, proliferation, and stress responses. Pharmacological inhibition of BET proteins with small molecules that disrupt bromodomain engagement with acetyllysine residues (such as JQ1) or drive their degradation through the ubiquitin–proteasome system (such as dBET6) ameliorates pathological gene expression in a range of systems and shows promise as a potential therapeutic strategy. Understanding the cell-type and signaling pathway requirements that dictate BET dependence in a particular cellular context remains incomplete. We previously demonstrated that, in neonatal rat cardiomyocytes, GPCR-induced hypertrophy responses depended strongly on the BET protein Brd4 when signaling was coupled to Gαs, but not Gαq. Here, we tested whether Brd4 was differentially responsive to G protein isoforms in HEK 293 cells by expressing Gαs- or Gαq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Gαq induced the expression of a group of early response genes and inflammatory genes in a manner largely insensitive to pharmacological BET inhibition, consistent with our previous data in cardiomyocytes. Gαs activated a small subset of the Gαq-induced genes, but this effect was largely reversed by dBET6. Our data further suggest that there may be general signaling requirements to activate Brd4 across cell types. Full article

Smooth muscle cell (SMC) differentiation plays a crucial role in angiogenesis and vasculogenesis during embryonic development. The underlying mechanisms controlling SMC differentiation, especially progenitor-specific regulation, however, remain largely unclear. In this study, we identified bromodomain-containing protein 4 (BRD4) as a novel regulator for SMC differentiation. Transforming growth factor-β (TGF-β) induces BRD4 expression in the initial phase of SMC differentiation of pluripotent murine 10T1/2 cells. BRD4 was found critical in mediating TGF-β-induced SMC differentiation. Knockdown of BRD4 with siRNA suppressed TGF-β-induced expression of SMC markers including α-SMA and SM22α. In addition, the BRD4 inhibitor JQ1 and degraders ARV-825 and dBET1 suppressed TGF-β-induced SMC marker gene expression. BRD4 regulates SMC differentiation by activating SMC marker gene transcription. BRD4 mediated SMC differentiation is independent of the phosphorylation of Smad2/3. Instead, BRD4 mediated TAZ expression induced by TGF-β. Consistent with the function of TAZ, the inhibition of BRD4 reduced nuclear retention of Smad3, thereby impairing Smad3 mediated SMC gene transcription. Myocardin is an important transcriptional modulator for SMC markers. Interestingly, the knockdown of BRD4 also attenuated the induction of myocardin due to TGF-β in 10T1/2 cells. Taken together, this study demonstrates that BRD4 is a novel modulator for SMC differentiation from mesenchymal progenitor cells through the regulation of TAZ and myocardin. Full article

Defects in lysosomal cholesterol handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann–Pick type C disease (NPCD), where cholesterol export from the endosomal–lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as new drug targets for NPCD using patient-derived skin fibroblasts. Treatment with JQ1, a prototype BET protein inhibitor, raised the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose-, time-, and patient-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by pharmacologic inhibition of NPC1 and of histone deacetylase (HDAC) activity, respectively. Taken together, bromodomain proteins should be further explored as therapeutic drug targets for lysosomal diseases like NPCD, and as new components regulating lysosomal function and cholesterol metabolism. Full article

Background: Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) proteins, including BRD4, are epigenetic modulators that regulate genes implicated in CLL pathogenesis and TME interactions. Previously, we investigated how the novel BET inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesize that BET proteins such as BRD4 regulate MDSC functions, and subsequent pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL. Methods: Utilizing the Eµ-TCL1 mouse model of CLL, we evaluated BRD4 protein expression in MDSCs derived from the bone marrow of transgenic and age-matched wild-type (WT) mice. We then investigated the ex vivo functionality of OPN5-treated MDSCs, expanded from Eµ-TCL1 and WT bone marrow in MDSC-supportive medium. Finally, we conducted an in vivo study utilizing the Eµ-TCL1 adoptive transfer mouse model to determine the in vivo effects of OPN5 on MDSCs and other immune populations. Results: Through the course of this study, we found that MDSCs isolated from Eμ-TCL1 mice upregulate BRD4 expression and are more immune-suppressive than their WT counterparts. Furthermore, we demonstrated ex vivo OPN5 treatment reverses the immune-suppressive capacity of MDSCs isolated from leukemic mice, evident via enhanced T-cell proliferation and IFNγ production. Finally, we showed in vivo OPN5 treatment slows CLL disease progression and modulates immune cell populations, including MDSCs. Conclusions: Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL. Full article

Background/Objectives: Metastatic prostate cancer (PCa) remains a major clinical challenge with limited therapeutic options. The long non-coding RNA H19 has been implicated in regulating cell adhesion molecules and collective migration, key features of metastatic dissemination. This study investigates the role of the Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 in the H19-dependent transcriptional regulation of cell adhesion molecules. Currently, the major effects of BET inhibitors require androgen receptor (AR) expression. Methods: H19 was stably silenced in PC-3 (AR-null) and 22Rv1 (AR-positive) castration-resistant PCa cells. The cells were treated with the pan-BET inhibitors JQ1 and OTX015 or the BET degrader dBET6. In vivo, the effects of JQ1 were evaluated in xenograft mouse models. Chromatin immunoprecipitation (ChIP) and RNA-ChIP were used to assess BET protein recruitment and interaction with cell adhesion gene loci and H19. Organotypic slice cultures (OSCs) from fresh PCa surgical specimens were used as ex vivo models to validate transcriptional changes and BRD4 recruitment. Results: BET inhibition significantly reduced the expression of β4 integrin and E-cadherin and cell proliferation in both basal conditions, and following H19 knockdown in PC-3 and 22Rv1 cells. These effects were mirrored in JQ1-treated tumor xenografts, which showed marker downregulation and tumor regression. ChIP assays revealed that BRD4, more than BRD2/3, was enriched on β4 integrin and E-cadherin promoters, especially in regions marked by H3K27ac. H19 silencing markedly enhanced BRD4 promoter occupancy. RNA-ChIP confirmed a specific interaction between BRD4 and H19. These findings were validated in OSCs, reinforcing their clinical relevance. Conclusions: Our study demonstrates that BRD4 epigenetically regulates the H19-mediated transcriptional control of adhesion molecules involved in collective migration and metastatic dissemination. Importantly, these effects are independent of AR status, suggesting that targeting the H19/BRD4 axis may represent a promising therapeutic avenue for advanced PCa. Full article

Salivary gland dysfunction is a hallmark of Sjögren’s disease (SjD). Here, we investigated the pro-inflammatory properties of salivary gland-derived fibroblasts (SGF) that were cultured from minor salivary gland (MSG) tissues of patients with SjD and controls. SGF from patients with SjD exhibited higher rates of proliferation compared to controls. RNA sequencing revealed pronounced pro-inflammatory properties of SGF in response to stimulation with IL1 and polyI:C, with an activation of “interferon responses”, “JAK STAT”, and “NF-kappa B” signaling, as well as ”complement” pathways. In addition to encoding pro-inflammatory transcripts, stimulated SGF featured increased expression of a number of non-coding enhancer RNAs (eRNAs) that we originally identified in TNF-stimulated synovial fibroblasts (FLS) by CAGE sequencing. We confirmed the expression of selected eRNAs in SGF and FLS through time-course experiments upon stimulation with different pro-inflammatory stimuli using real-time PCR. Furthermore, we detected eRNAs for IL6 (eIL6) and IL8 (eIL8#3) in MSG tissues. Treatment of SGF with the bromodomain inhibitor I-BET suppressed IL1- and LPS-induced expression of all eRNAs tested, as well as their associated pro-inflammatory coding transcripts. Transfection of SGF with antisense nucleotides targeting eCCL20 reduced the LPS-induced expression of this eRNA, as well as CCL20 expression and secretion. Together, our data highlight similarities between SGF and FLS regarding their activation under inflammatory conditions. Full article

Neuroinflammation is a key feature of all neurodegenerative disorders, including Alzheimer’s disease, and is tightly regulated by epigenetic mechanisms. Among them, bromodomain and extraterminal domain (BET) proteins play a crucial role by recognizing acetylated histones and acting as transcriptional co-regulators to modulate gene expression. This study investigates the potential of inhibiting BET proteins in preventing microglia-mediated neuronal damage in vitro. Murine BV2 microglial cells were exposed to lipopolysaccharide (LPS) or amyloid-β (Aβ) to induce an inflammatory response, and the subsequent effects on murine HT22 neuronal cells were examined. Among the BET proteins tested, only Brd4 was significantly upregulated in BV2 cells upon pro-inflammatory stimulation. JQ1, a potent pan-inhibitor of BET proteins, suppressed LPS-induced upregulation of pro-inflammatory cytokine mRNA levels, including Il1b, Il6, and Tnf, in BV2 microglia. Pre-treatment with JQ1 attenuated the cytotoxicity of LPS-activated BV2 cells toward neurons. Additionally, conditioned media from Aβ fibril-stimulated BV2 cells induced neuronal cell death, which was partially prevented by pre-treatment with JQ1. Co-culture assays further demonstrated the beneficial effect of BET inhibition. Our findings suggest that targeting BET proteins may offer a neuroprotective strategy by modulating microglial activation, potentially providing therapeutic benefits in neurodegenerative diseases. Full article

Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that recognize the histone acetylation code and play a critical role in regulating gene transcription. Dysregulation of BET proteins is associated with a number of pathologies, including cancer, inflammation-related metabolic disorders, etc. BET proteins can also be hijacked by some viruses and mediate latent viral infections, making BET proteins promising targets for therapeutic intervention. Research in this area has mainly focused on bromodomain inhibition, with less attention paid to other domains. Bromodomain inhibitors have great potential as anticancer and anti-inflammatory drug candidates. However, their broad-spectrum impact on transcription and potential cross-reactivity with non-BET bromodomain-containing proteins raise concerns about unforeseen side effects. Non-bromodomain BET inhibitors hold promise for gaining better control over the expression of host and viral genes by targeting different stages of BET-dependent transcriptional regulation. In this review, we discuss recent advances in the development of non-bromodomain BET inhibitors, as well as their potential applications, advantages, and perspectives. Full article