Histone Deacetylase Inhibitor Research Articles (Page 1)

Profilin-2 (PFN2) is implicated in cancer metastasis, yet its significance in oral squamous cell carcinoma (OSCC) is unclear. We quantified PFN2 mRNA and protein in 236 OSCC tumours using qRT-PCR and immunohistochemistry, correlating findings with clinicopathology and survival. Gain- and loss-of-function studies were performed in OSCC cell lines and xenograft mice. RNA sequencing with gene-set enrichment, subcellular fractionation, and immunofluorescence delineated PFN2-dependent pathways. Sensitivity to the histone deacetylase (HDAC) inhibitor SAHA was assessed in vitro. High PFN2 expression correlated with lymph-node metastasis, stage IV disease, and poorer overall and disease-free survival (p < 0.01). PFN2 increased proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and accelerated primary tumour growth plus cervical/lung metastasis in vivo; knockout produced opposite effects. Transcriptomics revealed enrichment of EMT, E2F, G2/M, and hypoxia signatures, with a 44% overlap with HDAC1 targets. PFN2 shifted HDAC1 to the cytoplasm and downregulated NuRD partners MBD3/MTA1 without altering total HDAC1. PFN2-driven EMT was independent of β-catenin nuclear entry. PFN2 overexpression sensitized cells to SAHA, enhancing G2/M arrest, apoptosis, and invasion blockade. PFN2 is an oncogenic driver that promotes OSCC progression through HDAC1-dependent transcriptional reprogramming. PFN2 may serve as a prognostic biomarker and predictor of response to HDAC-targeted therapy.

Pairing casino-inspired audiovisual cues with reward delivery significantly increases risky decision-making in laboratory-based gambling tasks across rats and humans. The neurocognitive mechanisms underlying this effect are unclear. Data from the rat gambling task (rGT) suggests win-paired cues render choice insensitive to reinforcer devaluation, indicating habitual control of decision-making. Histone deacetylase enzymes (HDACs) negatively mediate gene expression. Inhibiting this process can facilitate the formation of long-term memories and accelerate habit formation. We therefore hypothesised that risky decision making in the cued rGT could be enhanced by administration of the non-specific class I HDAC inhibitor sodium butyrate (NaBut). Male Long Evans rats received NaBut after each cued rGT session during task acquisition. NaBut-treated rats developed a bias towards the risky options more rapidly during the first five training sessions. Immunohistochemical analysis indicated a relative increase in histone acetylation in the striatum and prelimbic frontal cortex after five days of NaBut treatment. Modeling the data using previously established reinforcement learning algorithms optimised for the rGT suggests that NaBut concurrently increased learning from rewards while also decreasing learning from punishments during this early learning period. However, once training was complete, NaBut-treated animals were just as sensitive as controls to the omission of reward, although behavioural changes were less apparent in risk-preferring rats. These findings suggest that development of a maladaptive, risky strategy while learning the cued rGT can be facilitated through HDAC inhibition, but fall short of conclusively demonstrating that such treatment results in greater habitual control over behaviour.

Histone acetylation modification represents a common epigenetic regulatory mechanism, carrying out an indispensable role in cellular gene transcription and function. Histone deacetylases (HDACs) are responsible for regulating gene expression by controlling the deacetylation of histones and non‑histone proteins, and can serve as effective targets for participating in immune regulation. Short‑chain fatty acids (SCFAs) are important metabolites produced by the gut microbiota that modulate host immunity. SCFAs possess extensive inhibitory activities on class I and II HDACs, as well as acetylation‑modifying effects. Based on these, the present review initially introduces the microbial synthesis and intestinal absorption of SCFAs, as well as the classification and function of HDACs. Subsequently, the present review comprehensively summarizes the direct regulatory effects of SCFAs on immune cells through HDAC inhibition, encompassing innate immune cells (macrophages, dendritic cells, neutrophils, mast cells and natural killer cells) as well as T/B lymphocytes. Moreover, the present review further discusses the local intestinal and extra‑intestinal (primarily involving the liver, kidney, nerves and blood vessels) protective effects of SCFAs, which are mediated by their HDAC‑inhibiting activities. Finally, the present review summarizes the therapeutic potential of SCFAs as effective HDAC inhibitors in ameliorating intestinal and extra‑intestinal diseases and discusses the research prospects. The present review aims to elucidate the regulatory effects of SCFAs on host immunity through HDAC inhibition, highlighting their therapeutic potential for human diseases.

Histone deacetylase inhibitors (HDACi) and PROTACs are promising cancer therapies, but predictingtheir efficacy across different cell lines remains challenging. This study explores developing predictivemodels for HDACi and PROTAC responses using multi-omics data and machine learning. For HDACi, itis hypothesized that integrating genomic, transcriptomic, and proteomic data will identify biomarkers thatpredict drug-induced gene expression changes and response across cancer cell lines. The complexmodulation of histone and non-histone proteins by HDACi necessitates multi-omics approaches tounderstand their effects on cellular pathways. For PROTACs, it is hypothesized that machine learningmodels incorporating protein expression and degradation data will predict drug responses by identifyingkey proteins involved in the degradation process. PROTACs target previously "undruggable" proteinsthrough the ubiquitin-proteasome system. This model aims to enhance the precision of drug responsepredictions. By leveraging these data-driven approaches, this research seeks to optimize personalizedcancer therapies and improve treatment outcomes for HDACi and PROTAC-based therapies.

Short-chain fatty acids (SCFAs) produced from dietary fibre fermentation can regulate adipose tissue metabolism through signalling pathways involving G-protein-coupled receptors and histone deacetylase inhibition. While preclinical studies suggest they enhance thermogenesis, their role in human brown adipose tissue (BAT) under different thermal conditions remains unclear. This study explores the associations between circulating SCFAs and human BAT metabolism at room temperature and after cold exposure. This cross-sectional study included data from 71 adults (20-55 years, BMI 19-44 kg/m²). Dynamic [15O]O2, [15O]H2O, [¹⁸F]FDG, and [¹⁸F]FTHA PET/CT scans were used to assess BAT metabolism. Serum SCFAs were quantified using LC-MS, and gene expression in biopsy-excised BAT samples (n=14) was analysed. Participants were stratified into low- and high-BAT groups based on [¹⁸F]FDG or [¹⁸F]FTHA uptakes. Cold-induced acetate and propionate were positively associated with key in vivo BAT metabolism indicators, namely non-esterified fatty acids (NEFA) uptake and oxygen consumption. Only in the high-BAT group were circulating SCFAs maintained after cold exposure. BAT transcriptome revealed that genes involved in SCFA metabolism (such as conversion to acetyl-CoA) correlated with thermogenic and lipid metabolism genes exclusively in the high-BAT group, suggesting a distinct molecular link between SCFA pathways and BAT function. Circulating SCFAs are linked with BAT oxidative metabolism and NEFA uptake during cold exposure. The observed correlations between SCFA catabolic genes and thermogenic markers suggest that metabolically active BAT may selectively engage SCFA-related pathways, pointing to a potential mechanistic role of SCFAs in supporting BAT function in humans.

Histone deacetylases (HDACs) mediate the removal of acetyl groups from lysine residues in both histone and non-histone proteins, and have been regarded as promising targets for drug discovery. As a central member of HDAC family, HDAC1 has been found to be closely linked to the occurrence and development of prostate cancer. In this study, we designed and synthesized a new series of 3-phenylisoxazole HDAC1 inhibitors based on the hit 7, identified by in-house compound library screening. The structure-activity relationship studies (SARs) indicated that the R1 position was relatively tolerated for activity. The linker length at R2 exerted a significant influence on activity with the relative orders of butyl > propyl > ethyl > methyl. Among synthetic 16 compounds, compound 17 indicated the strongest HDAC1 inhibitory effect with the inhibition rate of 86.78% at the concentration of 1000 nM. In addition, derivative 17 could not only well occupy the active pocket of HDAC1, but also showed favorable drug-like properties. More importantly, molecule 17 exerted potent anti-proliferative activity on prostate cancer PC3 cells with the IC50 value of 5.82 μM, and had no significant toxicity against normal prostate WPMY-1 cells. Collectively, these findings validate phenylisoxazole derivative 17 as a promising lead compound for further optimization and development.

Histone deacetylases (HDACs) mediate the removal of acetyl groups from lysine residues in both histone and non-histone proteins, and have been regarded as promising targets for drug discovery. As a central member of HDAC family, HDAC1 has been found to be closely linked to the occurrence and development of prostate cancer. In this study, we designed and synthesized a new series of 3-phenylisoxazole HDAC1 inhibitors based on the hit 7, identified by in-house compound library screening. The structure-activity relationship studies (SARs) indicated that the R1 position was relatively tolerated for activity. The linker length at R2 exerted a significant influence on activity with the relative orders of butyl > propyl > ethyl > methyl. Among synthetic 16 compounds, compound 17 indicated the strongest HDAC1 inhibitory effect with the inhibition rate of 86.78% at the concentration of 1000 nM. In addition, derivative 17 could not only well occupy the active pocket of HDAC1, but also showed favorable drug-like properties. More importantly, molecule 17 exerted potent anti-proliferative activity on prostate cancer PC3 cells with the IC50 value of 5.82 μM, and had no significant toxicity against normal prostate WPMY-1 cells. Collectively, these findings validate phenylisoxazole derivative 17 as a promising lead compound for further optimization and development.

Purpose Hyperactivation of the PI3K/AKT/mTOR pathway promotes tumor progression in many cancers. Among these, endometrial cancer (EC) exhibits the highest frequency of alterations in this pathway, making it an ideal model for targeted treatment. Progestin therapy is initially effective, but advanced EC often resists treatment due to loss of progesterone receptor (PR) and acquired resistance. Furthermore, as obesity is the main etiological driver of EC, obesity-related factors activate the PI3K/AKT pathway and inhibit PR function. Therefore, there is a clinical need to identify therapies that enhance progestin sensitivity by upregulating PR, downregulating obesity-related factors, and inhibiting the PI3K/AKT pathway. Methods A dual HDAC (histone deacetylase) and PI3K inhibitor, CUDC-907 (fimepinostat), was tested for its ability to inhibit the proliferation of endometrial cancer cells both in vitro and in vivo by targeting PI3K and HDAC pathways. A WST-1 Cell Proliferation Colorimetric Assay Kit was used to assess cell viability. Western blotting was used for protein expression. Endometrial cancer xenograft models were established in mice fed a high-fat-diet, normal chow, or subjected to fasting to evaluate the drug’s activity under different metabolic conditions. Serum biomarkers were quantified using enzyme-linked immunosorbent assay (ELISA). Results Rapid inhibition of the PI3K/AKT pathway was observed; CUDC-907 treatment downregulated p-AKT, p-rS6, and p-4EBP1. Concurrently, transcriptional inhibition of HDAC activity was also observed. PR expression was restored, downstream genes FOXO1, p21, and H3Ace were upregulated, and oncogenes Myc and HER2 (Neu/ErbB2) were downregulated. CUDC-907 induced both intrinsic and extrinsic apoptotic pathways. In vivo , CUDC-907 inhibited EC progression, increased survival of tumor-bearing mice, and suppressed tumor growth. Notably, CUDC-907 was most effective in reducing tumor growth in mice on high-fat diets. Furthermore, serum IGF-1 levels decreased following CUDC-907 treatment, suggesting that IGF-1 may serve as a surrogate serum marker for the CUDC-907 drug’s effect in EC. Conclusion Our findings suggest that CUDC-907 is a promising agent that can re-sensitize tumors to progestin therapy and improve outcomes for EC patients. This study supports CUDC-907 as a potent treatment strategy in endometrial cancer and identifies IGF-1 as a potential surrogate serum biomarker for therapeutic response.

Histone deacetylases (HDACs) play a crucial role in gene expression, and their dysregulation is linked to various cancers. HDAC inhibitors, particularly hydroxamic acid derivatives, have shown promising anticancer effects, with several approved for clinical use. This research aimed to synthesize novel 7-hydroxycoumarin-based N-hydroxyamides, evaluate their HDAC inhibition, and assess their in vitro cytotoxic effects. The structures of the synthesized compounds were established by analysis of their physicochemical, elemental, and spectroscopic data. HDAC, in vitro assays, and molecular docking were performed using standard procedures. The biological results showed that compounds 5d, 5e, 5j, 5l, and 7k exhibited potential cytotoxicity toward all five cancer cell lines. These compounds displayed potent cytotoxicity against the NCCIT cancer cell line with IC50 values of 4.53-1.45 μM. However, they exhibited weak to medium HDAC inhibitory activity with IC50 values ranging from 21.72 to 4.79 μM. Docking simulation studies with selected compounds revealed that compounds 5a and 7k formed stable interactions in the active site of HDAC enzyme with binding affinities ranging from -7.43 to -7.103 kcal/mol, respectively. The study revealed several compounds with potential HDAC inhibitory activity and cytotoxicity. However, they were still less effective in inhibiting HDACs than SAHA and Trichostatin A. Their reduced potency may be related to the length of the linker linked to the surface recognition group. This provides important insight into the future design of hydroxamic acids of this type. The research results suggest that some hydroxamic acids (5a and 7k) warrant further evaluation, and these results could serve as a basis for designing more potent HDAC inhibitors and antitumor agents.

Although histone deacetylase (HDAC) inhibitors have demonstrated significant advantages in the field of targeted cancer therapy, numerous adverse events have been observed due to the high doses required to achieve therapeutic effects. Additionally, acquired drug resistance to HDAC inhibitors has also been observed in clinical usage. Given these findings, the development of HDAC degraders may represent a more promising strategy to overcome these limitations due to their specific mechanism of action. In this study, 14 HDAC degraders featuring a polyamine linker are designed and synthesized by conjugating HDAC inhibitors (HDACi, Vorinostat) with Cereblon (CRBN, an E3 ubiquitin ligase ligand). Significantly, compound I exhibited a degradation efficiency of ≈62% at 5 μM in MDA-MB-231 cells. Additionally, compound N exhibited the highest cellular uptake efficiency in a dose- and time-dependent manner. The findings presented in our manuscript provided valuable insights for the development of a proteolysis targeting chimera with high cellular uptake efficiency.

Histone deacetylases (HDACs) play a crucial role in the regulation of cancer progression and have emerged as key targets for antitumor therapy. Histone Deacetylase Inhibitors (HDACis) effectively suppress tumor cell proliferation, induce apoptosis, and cause cell cycle arrest, demonstrating broad-spectrum antitumor activity. This article primarily focuses on enhancing the selectivity of HDACis through structural modification using natural compounds. It provides detailed insights into the structure modification of histone deacetylase 8 (HDAC8) and histone deacetylase 10 (HDAC10), as well as dual-- target inhibitors and their pharmacological effects. Furthermore, conventional HDAC inhibitors are susceptible to off-target effects and the development of drug resistance. Our research focuses on augmenting the targeting specificity of HDAC inhibitors through their combination with proteolysis targeting chimera (PROTAC). Lastly, the latest advancements in clinical research on HDAC inhibitors were summarized, revealing that these inhibitors possess limitations in their clinical applications due to intrinsic or acquired resistance. Consequently, this article primarily focuses on summarizing the current status and prospects of structural modifications for HDAC inhibitors, with the aim of inspiring researchers to develop novel HDAC inhibitors exhibiting enhanced activity for improved application in clinical research.

ABSTRACTThe prognosis of metastatic castration‐resistant prostate cancer (mCRPC) remained unsatisfactory currently. Chidamide is a well tolerated, selective histone deacetylase (HDAC) inhibitor, but the efficacy in mCRPC remained uncertain. From August 2020 to October 2022, a total of 18 patients were enrolled. The primary endpoint was to assess the safety and the secondary endpoints including efficacy and biomarker analysis. The common adverse events (AEs) included anemia, anorexia, hypoalbuminemia, hyponatremia, nausea and fatigue. Grade 3 toxicities included anemia and thrombocytopenia, and no DLT was observed in this study. The median progression‐free survival (PFS) was 3.7 months (95% CI, 0.922–6.611 months), and the median OS was 11.0 months (95% CI, 2.232–19.768 months). The results of the RNA‐seq profile indicated the high immune cell infiltration and the upregulation of immune cell functions in tumor tissues was associated with the efficacy of chidamide, as revealed by GSEA and ssGSEA. Furthermore, chidamide has been demonstrated to upregulate immune response‐related pathways in CRPC cells. Our study suggested that chidamide plus abiraterone is well tolerated in mCRPC, and preliminary evidence suggests that it may improve the survival of patients with mCRPC. Furthermore, combining chidamide with immunotherapy could be another promising option for further enhancing its efficacy.

Unlocking the Therapeutic Potential of HDAC Inhibitors in Colorectal Cancer: Mechanisms, Efficacy, and Future Perspectives.

Targeting histone deacetylase 1: Inhibition and activation as promising therapeutic strategies for diverse disorders.

Lactiplantibacillus plantarum BD7807 ameliorates high-fat diet-induced lipid metabolic disorders and intestinal dysfunction via SCFAs-GPR43 pathway.

Panobinostat-Loaded Albumin Nanoparticles for the Treatment of Pancreatic Cancer.

Neuroregulatory effect of royal jelly.

Decoding the AML1/ETO translocation cipher: In-depth exploration into the pathogenesis and cutting-edge therapeutic strategies of t(8;21) acute myeloid leukemia.

The novel selective HDAC1 inhibitor ZJH-1 exhibits potent antitumor activity in castration-resistant prostate cancer, potentially involving HSP90AA1.

CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling.