Search Results (153)

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. 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

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel regulator of complement components and investigates its interaction with histone deacetylase 6 (HDAC6) in the context of therapeutic targeting. Methods: KYNU expression, and its association with complement signaling in GBM, were analyzed using publicly available datasets (TCGA, GTEx, HPA). Pathway enrichment was performed via LinkedOmics. In vitro studies in GBM cell lines (U87, U251, T98G) assessed the effects of KYNU silencing and treatment with an HDAC6 inhibitor (tubastatin) and a BET inhibitor (apabetalone) on gene expression and cell viability. Results: Bioinformatic analyses revealed significant overexpression of KYNU in GBM tissues compared to normal brain tissue. KYNU expression was positively associated with genes involved in complement and coagulation cascades. In vitro experiments demonstrated that KYNU silencing reduced the expression of C3, C3AR1, and C5AR1 and suppressed GBM cell viability. Treatment with tubastatin, while reducing viability, paradoxically upregulated complement genes, suggesting potential limitations in therapeutic efficacy. However, this effect was mitigated by KYNU knockdown. Combined treatment with apabetalone and tubastatin effectively suppressed KYNU expression and enhanced cytotoxicity, particularly in cells with high complement expression. Conclusions: Our findings establish the KYNU–HDAC6–complement axis as a critical regulatory pathway in GBM. Targeting KYNU-mediated complement activation through combined epigenetic approaches—such as HDAC6 and BET inhibition—represents a promising strategy to overcome complement-driven resistance in GBM therapy. Full article

Head and neck squamous cell carcinoma (HNSCC) remains challenging to treat despite multimodal therapeutic approaches. Cisplatin treatment is effective and cost-efficient, although chemoresistance and disease recurrence limit its efficacy. Understanding the mechanisms of cisplatin resistance and the identification of compounds to target resistant tumor cells are critical for improving patient outcomes. We have demonstrated that cisplatin-induced senescent HN30 HNSCC cells can be eliminated by ABT-263 (navitoclax), a BCL-2/BCL-X_L inhibitor that has senolytic properties. Here, we report the development of a cisplatin-resistant cell line (HN30R) for the testing of ABT-263 and the PROTAC BET degraders ARV-825 and ARV-771. ABT-263 was ineffective in sensitizing HN30R cells to cisplatin, largely due to a lack of senescence induction. However, the BET degraders in combination with cisplatin promoted apoptotic cell death in both HN30 and HN30R cells. The effectiveness of ARV-825 did not appear to depend on the cells entering into senescence, indicating that it was not acting as a conventional senolytic. ARV-825 treatment downregulated BRD4 and its downstream targets, c-Myc and Survivin, as well as decreased the expression of RAD51, a DNA repair marker. These results suggest that the BET degraders ARV-825 and ARV-771 may be effective in improving the response of chemoresistant head and neck cancer to cisplatin treatment. Full article

Marine biofouling, the process of marine microorganisms, algae, and invertebrates attaching to and forming biofilms on ship hulls, underwater infrastructure, and marine equipment in ocean environments, severely impacts shipping and underwater operations by increasing fuel consumption, maintenance costs, and corrosion risks, and by threatening marine ecosystem stability via invasive species transport. This study reports the development of a hydrogel-metal-organic framework (MOF)-quorum sensing inhibitor (QSI) antifouling coating on 304 stainless steel (SS) substrates. Inspired by mussel adhesion, a hydrophilic bionic hydrogel was first constructed via metal ion coordination. The traditional metal ion source was replaced with a zeolitic imidazolate framework-8 (ZIF-8) loaded with 2-(5H)-furanone (HF, a QSI) without altering coating formation. Physicochemical characterization using Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), the Brunauer–Emmett–Teller (BET) method, and the diffraction of x-rays (XRD) confirmed successful HF loading into ZIF-8 with intact crystal structures. Antifouling tests showed HF@ZIF-8 enhanced antibacterial inhibition against Staphylococcus aureus (97.28%) and Escherichia coli (>97%) and suppressed Chromobacterium violaceum CV026 pigment synthesis at 0.25 mg/mL (sub-growth concentration). The reconstructed PG/PVP/PEI/HF@ZIF-8 coating achieved 72.47% corrosion inhibition via synergistic anodic protection and physical shielding. This work provides a novel green approach for surface antifouling and drag reduction, highlighting MOF-loaded QSIs as promising additives to enhance the antifouling performance of hydrogel coatings, anti-corrosion performance, and QSI performance for sustainable marine engineering applications. 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

Oral cancer ranks in the top 10 most prevalent malignancies worldwide. It is an aggressive tumor with frequent relapses and metastases and relatively modest survival rates that do not improve in spite of constantly evolving treatment modalities. Cancer stem cells are a subpopulation of tumor cells considered to be responsible not only for tumor initiation but also its aggressive behavior. Many efforts are directed at targeting those cells specifically. A class of small molecules, inhibitors of BET proteins (iBET), is emerging as a novel anticancer tool. Modulating the expression of microRNAs could also be a valid approach in cancer therapy. We aimed to study the effect of the iBET JQ1 combined with miR-21 silencing on oral cancer stem cells (CD44+ cells). CD44+ cells were sorted by flow cytometry and treated with JQ1 alone or in combination with miRNA-21 silencing. Following treatment, MTT, spheroid formation, invasion, and annexin V assays were performed, along with cell cycle and gene expression analyses. JQ1 in conjunction with miR-21 silencing showed considerable cytotoxicity led to a significant downregulation of cyclin D1, consistent with G1 cell cycle arrest, a significant caspase 3 upregulation in accordance with activation of apoptosis. The combined treatment approach also reduced CD44+ cell invasion capacity. Modulating chromatin structure with iBETs and silencing miRNA could be suitable epigenetic adjuncts to oral cancer treatment. Full article

The compounds targeting the bromo and extra terminal domain proteins (BET), such as the JQ1, present potent anti-cancer activity in preclinical models, however, the application of JQ1 at the clinical level is limited by its short half-life, rapid clearance, and non-selective inhibition of BET family proteins, leading to off-target effects and resistance. To address these challenges, the optimization of JQ1 delivery has been accomplished through polylactide (PLA) nanoparticles. PLA derivatives with varying molecular weights were synthesized via ring-opening polymerization using a zinc-based initiator and characterized using thermogravimetric analysis, differential scanning calorimetry, and infrared spectroscopy. PLA nanoparticles (NPs) were subsequently formulated, and the effects of key parameters—including PLA molecular weight, organic phase concentration, and surfactant concentration—on particle size, polydispersity index (PDI), and encapsulation efficiency were systematically investigated. PLA molecular weight and organic phase concentration mainly influenced the NPs size whilst the thermodynamic state of the NPs was unaffected by these two parameters. The surfactant concentration is correlated to the encapsulation efficacy of JQ1 as well as the release profile, suggesting the potential tool that the variation of these parameters represent for customizing the release of JQ1 according to specific needs. Full article

2-deoxy-D-glucose (2DG) is a glycolysis and protein N-glycosylation inhibitor with promising anti-tumor and immunomodulatory effects. However, 2DG can also suppress T cell function, including IFN-γ secretion. Few human T cell studies have studied low-dose 2DG, which can increase IFN-γ in a Jurkat clone. We therefore investigated 2DG’s effect on IFN-γ in activated human T cells from PBMCs, with 2DG treatment commenced either concurrently with activation or 48 h after activation. Concurrent 2DG treatment decreased IFN-γ secretion in a dose-dependent manner. However, 2DG treatment of pre-activated T cells had a hormetic effect on IFN-γ, with 0.15–0.6 mM 2DG (achievable in vivo) increasing and >2.4 mM 2DG reducing its secretion. In contrast, IL-2 levels declined monotonously with increasing 2DG concentration. Lower 2DG concentrations reduced PD-1 and increased CD69 expression regardless of treatment timing. The absence of increased T-bet or Eomes expression or IFNG transcription suggests another downstream mechanism. 2DG dose-dependently induced the unfolded protein response, suggesting a possible role in increased IFN-γ secretion, possibly by increasing the ER folding capacity for IFN-γ via increased chaperone expression. Overall, low-dose, short-term 2DG exposure could potentially improve the T cell anti-tumor response. Full article