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At least 19 recordsLinked to original sources
PubMed2026

Histone deacetylases: From acetylation homeostasis to oncogenic and neurodegenerative disorders.

Histone deacetylases (HDACs) are central regulators of acetylation homeostasis, governing chromatin architecture, transcriptional dynamics, and diverse cellular processes through reversible lysine deacetylation. Dysregulation of HDAC activity disrupts epigenetic balance and is strongly implicated in oncogenic transformation and the progression of neurodegenerative disorders. This chapter provides a comprehensive overview of HDAC biology with a particular emphasis on experimental and analytical methodologies used to investigate their function. We describe the structural and functional diversity of HDAC classes and their roles in multiprotein complexes that regulate gene expression and cellular signaling. A major focus is placed on screening-compatible and mechanistic assays, including fluorometric, colorimetric, radiometric, fluorescence polarization, TR-FRET, AlphaScreen/AlphaLISA, and differential scanning fluorimetry approaches for quantitative measurement of enzymatic activity and inhibitor profiling. In addition, advanced methodologies such as mass spectrometry-based acetylome analysis, chromatin immunoprecipitation sequencing (ChIP-seq), recombinant enzyme assays, and cell-based reporter systems are discussed in the context of functional genomics and drug discovery. The integration of high-throughput screening, structural biology, and multi-omics strategies is highlighted as essential for dissecting HDAC-mediated regulatory networks. Collectively, this chapter serves as a methodological framework for studying HDAC function and developing targeted epigenetic therapies in cancer and neurodegenerative diseases.

Histone Deacetylases↗
PubMed2025

Nitric oxide delays floral transition in Arabidopsis by inhibiting histone deacetylases HDA5 and HDA6.

Nitric oxide (NO), a reactive small molecule, plays a critical role in various developmental and physiological processes in living organisms. Previous studies by our group revealed that NO delays flowering in Arabidopsis by increasing transcript levels of the flowering repressor FLOWERING LOCUS C (FLC). In this study, we further investigated the molecular mechanism by which NO regulates FLC expression. Genetic experiments demonstrated that NO-induced delayed flowering specifically depends on elevated FLC transcript levels. Chromatin Immunoprecipitation assays revealed that NO significantly enhances histone H3 acetylation at the FLC locus. Biochemical analyses further showed that NO reduces total histone deacetylase activity through S-nitrosylation of histone deacetylases HDA5 and HDA6. Additionally, we identified and evaluated potential S-nitrosylation sites on HDA5 and HDA6, revealing their effects on deacetylase activity and floral regulation. Collectively, our findings uncover a novel mechanism by which NO mediates epigenetic modification to modulate flowering in Arabidopsis. This study sheds light on the functional network linking NO signaling, epigenetic modification, and flowering.

Arabidopsis↗
PubMed2026

Characterization and functional insights of histone deacetylases in bivalves: implications for temperature and immune response in Chlamys nobilis.

Histone deacetylases serve as pivotal epigenetic regulators that modulate chromatin remodeling and gene transcription, playing critical roles in immune defense and environmental stress responses in aquatic organisms. However, the evolutionary characteristics and functional roles of the HDAC family in bivalves remain poorly understood. In this study, genome-wide identification of the HDAC family across 30 bivalve species yielded 558 HDAC genes. Phylogenetic reconstruction categorized these genes into four conserved groups and revealed a unique, bivalve-specific SIRT8 clade. Using the noble scallop Chlamys nobilis as a representative model, expression profiling revealed distinct expression patterns among CnHDAC members. Class I and most Class III members were predominantly expressed in the gonads, while Class II members were enriched in immune-related tissues, implying their potential involvement in bivalve immunity. Upon temperature stress, CnHDAC1/2, CnHDAC11-1, CnHDAC11-2, CnSIRT2-1, CnSIRT4, CnSIRT6, and CnSIRT8-3 were significantly induced, highlighting their critical roles in temperature adaptation. Upon Vibrio exposure, CnHDAC1/2, CnHDAC8, CnSIRT4, and CnSIRT6 were upregulated, while CnHDAC4/5/7/9, CnHDAC6/10, CnSIRT2-2, CnSIRT5, CnSIRT7, and CnSIRT8-3 were downregulated, suggesting a coordinated epigenetic regulatory mechanism underlying host immune defense. In conclusion, this study systematically elucidates the evolutionary landscape of the HDAC family and underscores its potential involvement in environmental resilience and host immunity, providing a theoretical basis for the breeding of disease-resistant and stress-tolerant aquaculture bivalves.

Animals↗
PubMed2005

Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1.

The growth factor independent 1 (Gfi1) transcriptional regulator oncoprotein plays a crucial role in hematopoietic, inner ear, and pulmonary neuroendocrine cell development and governs cell processes as diverse as self-renewal of hematopoietic stem cells, proliferation, apoptosis, differentiation, cell fate specification, and oncogenesis. However, the molecular basis of its transcriptional functions has remained elusive. Here we show that Gfi1 recruits the histone lysine methyltransferase G9a and the histone deacetylase 1 (HDAC1) in order to modify the chromatin of genes targeted for repression by Gfi1. G9a and HDAC1 are both in a repressive complex assembled by Gfi1. Endogenous Gfi1 colocalizes with G9a, HDAC1, and K9-dimethylated histone H3. Gfi1 associates with G9a and HDAC1 on the promoter of the cell cycle regulator p21Cip/WAF1, resulting in an increase in K9 dimethylation at histone H3. Silencing of Gfi1 expression in myeloid cells reverses G9a and HDAC1 recruitment to p21Cip/WAF1 and elevates its expression. These findings highlight the role of epigenetics in the regulation of development and oncogenesis by Gfi1.

Cell Line, Tumor↗
PubMed2010

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1.

RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.

Amphiregulin↗
PubMed2026

HDAC inhibition via suberoylanilide hydroxamic acid ameliorates doxorubicin-induced cardiotoxicity.

Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIb has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with the pathological cardiac response. Here, we show that doxorubicin promotes topoisomerase IIb accumulation at cardiomyocyte-specific gene promoters (e.g., Actc1, Myl2, and Myh7) overlapping myocyte enhancer factor 2 binding sites and enhances myocyte enhancer factor 2 -dependent transcription. This response is attenuated by the pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid -mediated cardioprotection requires class IIa histone deacetylases, as genetic loss of HDAC4 abolishes its effect. Mechanistically, suberoylanilide hydroxamic acid induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing myocyte enhancer factor 2 - driven transcription. In vivo, suberoylanilide hydroxamic acid mitigates doxorubicin-induced cardiotoxicity. These findings identify histone deacetylase inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity.

Doxorubicin↗
PubMed2024

Reversion from basal histone H4 hypoacetylation at the replication fork increases DNA damage in FANCA deficient cells.

The FA/BRCA pathway safeguards DNA replication by repairing interstrand crosslinks (ICL) and maintaining replication fork stability. Chromatin structure, which is in part regulated by histones posttranslational modifications (PTMs), has a role in maintaining genomic integrity through stabilization of the DNA replication fork and promotion of DNA repair. An appropriate balance of PTMs, especially acetylation of histones H4 in nascent chromatin, is required to preserve a stable DNA replication fork. To evaluate the acetylation status of histone H4 at the replication fork of FANCA deficient cells, we compared histone acetylation status at the DNA replication fork of isogenic FANCA deficient and FANCA proficient cell lines by using accelerated native immunoprecipitation of nascent DNA (aniPOND) and in situ protein interactions in the replication fork (SIRF) assays. We found basal hypoacetylation of multiple residues of histone H4 in FA replication forks, together with increased levels of Histone Deacetylase 1 (HDAC1). Interestingly, high-dose short-term treatment with mitomycin C (MMC) had no effect over H4 acetylation abundance at the replication fork. However, chemical inhibition of histone deacetylases (HDAC) with Suberoylanilide hydroxamic acid (SAHA) induced acetylation of the FANCA deficient DNA replication forks to levels comparable to their isogenic control counterparts. This forced permanence of acetylation impacted FA cells homeostasis by inducing DNA damage and promoting G2 cell cycle arrest. Altogether, this caused reduced RAD51 foci formation and increased markers of replication stress, including phospho-RPA-S33. Hypoacetylation of the FANCA deficient replication fork, is part of the cellular phenotype, the perturbation of this feature by agents that prevent deacetylation, such as SAHA, have a deleterious effect over the delicate equilibrium they have reached to perdure despite a defective FA/BRCA pathway.

Histones↗
PubMed1978

Suppression of histone deacetylation in vivo and in vitro by sodium butyrate.

In HeLa cells which have been exposed to 5 mM sodium butyrate for 21 h, the level of histone acetylation is greatly increased as compared to control cells (Riggs, M.G., Whittaker, R.G., Neumann, J.R., and Ingram, V.R. (1977) Nature 268, 462-464). Our experiments indicate that the increase in the relative amounts of multiacetylated forms of histones H4 and H3 following butyrate treatment is the result of an inhibition of histone deacetylase activity.

Butyrates↗
PubMed2026

Alternative oxidase pathway inhibits PuWRKY7-PuHDAC15 complex to promote ester aroma synthesis in Nanguo pear.

Volatile esters are key contributors to the characteristic aroma in fruit, and their accumulation directly dictates fruit quality and consumer acceptance. The alternative oxidase pathway is known for its role in regulating fruit quality, but its molecular mechanism in ester aroma accumulation remains unclear. Here, we demonstrated that the alternative oxidase pathway acts as the dominant respiratory pathway in Nanguo pear (Pyrus ussuriensis) during ripening and promotes ester aroma accumulation by increasing histone acetylation levels of PuAAT1 (alcohol acetyltransferase 1), the key gene governing ester synthesis. Further, we identified PuHDAC15 as a critical histone deacetylase that modulates acetylation levels and interacts with the transcription factor PuWRKY7. Mechanistically, PuWRKY7 directly binds to the W-box elements in the PuAAT1 promoter. The PuHDAC15-PuWRKY7 complex acts synergistically to repress PuAAT1 transcription, thereby decreasing its histone acetylation levels and gene expression, and consequently inhibiting ester aroma accumulation in Nanguo pear. This study reveals how the alternative oxidase pathway integrates into fruit aroma formation via epigenetic regulation and gene expression, thereby providing a scientific basis for targeted improvement of fruit quality.

Plant Proteins↗
PubMed1978

Sodium butyrate inhibits histone deacetylation in cultured cells.

Sodium butyrate in millimolar concentrations causes an accumulation of acetylated histone species in a variety of vertebrate cell lines. In all lines tested, butyrate caused hyperacetylation of H3 and H4, and in rat IRC8 cells, H2A and H2B were also affected. In Friend erythroleukemic cells, butyrate also induces the synthesis of a nonhistone chromosomal protein, IP25. butyrate does not affect the rate of histone acetylation in cell-free extracts of nuclei of Friend cells. Rather, this fatty acid inhibits histone deacetylation. Cell-free extracts of either control cells or butyrate-grown cells contain comparable levels of histone-deacetylating activity. This in vitro activity is inhibited by the addition of butyrate to the extracts. Thus butyrate appears to be an inhibitor of histone deacetylases both in vivo and in vitro.

Acetylation↗
PubMed2026

Comprehensive mass spectrometry screening-derived atlas of HDAC inhibitors reveals histone-specific acetylation changes.

Histone deacetylase inhibitors (HDACis) have emerged as valuable therapeutics for cancer and other diseases; however, their effects on histone post-translational modification remain poorly characterized. Here, we applied quantitative mass spectrometry and high-throughput sequencing to systematically profile site-specific changes in histone modifications in response to a panel of HDACis. This platform enabled mapping of histone modification changes across hundreds of sites, including low-abundance histone marks. Furthermore, an integrative analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) data identified genome-wide binding sites for the low-abundance histone modification of H2A.Z acetylation in HeLa and MDA-MB-231 breast cancer cells, highlighting the role of H2A.Z acetylation in regulating gene expression across diverse biological pathways, including specific genes involved in tumor suppressor pathways. Our findings provide a functional resource for identifying and quantifying histone modification changes and transcriptional regulation of histone H2A.Z acetylation following pharmacological perturbation.

Histone Deacetylase Inhibitors↗
PubMed1978

The effect of sodium butyrate on histone modification.

The hyperacetylation of histones due to treatment of cultured cells with sodium butyrate has been studied. The hyperacetylation is due to inhibition of histone deacetylase. Other short chain fatty acids including acetic, isobutyric and propionic acid also produce increased modification. Histone H4 already deposited on the chromosome can be rapidly acetylated to the extent of about 70%. That 80% of histone H4 is acetylated after a 24 hr exposure to butyrate is due to the fact that incoming H4 histone is 100% acetylated and does not return to the parental unmodified form in the presence of butyrate.

Acetates↗
PubMed2026

HDAC6 inhibition reduces Pseudomonas aeruginosa adherence and internalization in cystic fibrosis epithelial cells via microtubule stabilization.

Pseudomonas aeruginosa is a common opportunistic pathogen that causes chronic lung infections in individuals with cystic fibrosis. Despite advances in therapies that restore cystic fibrosis transmembrane conductance regulator function, persistent colonization of the airway remains a major clinical challenge. Reduced clearance of P. aeruginosa from the cystic fibrosis airway has been associated with the increased activity of histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase that decreases microtubule acetylation and stability. In this study, we investigated the role of HDAC6 in modulating interactions between P. aeruginosa and cystic fibrosis airway epithelial cells. Pharmacologic inhibition of HDAC6 significantly reduced bacterial adherence in both mouse and human cystic fibrosis epithelial cells. Genetic deletion of HDAC6 produced similar effects, while knockout of a microtubule-stabilizing protein increased bacterial adherence, mimicking the cystic fibrosis phenotype. HDAC6 inhibition also reduced bacterial internalization, although to a lesser extent compared to adherence. These results suggest that microtubule destabilization contributes to the enhanced colonization of cystic fibrosis airways by P. aeruginosa. Targeting host microtubule regulatory pathways, particularly by inhibiting HDAC6, may represent a promising host-directed strategy to limit early bacterial attachment and reduce the risk of chronic infection in cystic fibrosis.

Pseudomonas aeruginosa↗
PubMed2024

Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.

Animals↗
PubMed2026

Transcriptomic and network analyses identify epigenetic regulators of drug-tolerant persister (DTP) subsets in EGFR-mutant HCC827 non-small cell lung cancer.

BACKGROUND: The clinical efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by the inevitable acquired resistance. Drug-tolerant persister (DTP) cells, which survive initial therapy, are considered a key reservoir for this resistance. Understanding the molecular characteristics of DTPs is essential for developing strategies to prevent relapse. OBJECTIVE: This study aimed to characterize the transcriptomic landscape of osimertinib-tolerant DTP cells and identify key epigenetic regulators associated with the DTP phenotype in EGFR-mutant HCC827 NSCLC cells through integrated transcriptomic and network analyses. METHODS: We established an in vitro model of osimertinib tolerance using an EGFR-mutant (exon 19 deletion) HCC827 NSCLC cell line. Parental HCC827 cells and DTP subsets were subjected to transcriptomic analysis by RNA sequencing (RNA-seq). Differentially expressed genes were identified, followed by bioinformatics analyses, including Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses to identify key biological processes driving the DTP phenotype. Key findings were validated using quantitative real-time PCR (qPCR). RESULTS: Osimertinib treatment induced a morphologically distinct DTP population. Transcriptomic profiling revealed a marked shift in gene expression compared to parental cells. Functional enrichment analysis showed significant upregulation of epigenetic pathways. PPI network analysis identified a core module of eight hub genes, including histone deacetylases (HDAC5, HDAC9), sirtuins (SIRT1, SIRT2), and histone acetyltransferase (KAT2B). qPCR confirmed increased expression of HDAC5, HDAC9, and SIRT1. CONCLUSION: Epigenetic reprogramming accompanies the transition to an osimertinib-tolerant state in EGFR-mutant HCC827 cells. Targeting HDACs and sirtuins may represent a promising strategy to eliminate DTP subpopulations and delay or prevent acquired resistance.

Drug-tolerant persister↗
PubMed2026

Regulation of the lncRNA NEAT1 by p53-ΔNp63 crosstalk modulates the DNA damage response and therapeutic efficacy in HNSCC.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by recurrent genetic alterations, including the inactivation of the tumor suppressor TP53 gene and dysregulation of the TP63 gene. The TP63 gene encodes multiple isoforms, among which the N-terminal truncated isoform ΔNp63 is fundamental for the integrity of stratified epithelial tissues. We previously demonstrated that ΔNp63 represses the expression of the lncRNA NEAT1. Here, we investigated the functional crosstalk between p53 and ΔNp63 in modulating NEAT1 expression following genotoxic stress. We found that upon genotoxic insults, p53 activation and the concomitant downregulation of ΔNp63 promote NEAT1 transcription. In p53-proficient HNSCC cells, NEAT1 targeting leads to increased DNA damage, highlighting its potential role in maintaining genomic stability and facilitating efficient DNA repair. Importantly, we showed that histone deacetylase inhibitors (HDACis) upregulate NEAT1 expression independently of p53, and NEAT1 silencing enhances HDACis-induced DNA damage. Overall, our findings establish NEAT1 as an early regulator of the DNA damage response in HNSCCs and suggest that combining NEAT1 targeting with HDAC inhibition may potentiate therapeutic efficacy, particularly in TP53-mutant HNSCCs.

DNA damage↗
PubMed2026

Therapeutic Potential of Terpenes in Lung Cancer: Modulation of 4-Oxo- Retinoic Acid, TNF-α, NF-κB, and HDAC2 Pathways.

Non-small cell lung cancer (NSCLC) includes various epithelial malignancies, such as squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Despite advancements in surgical resection, chemoradiotherapy, and multimodal therapies, NSCLC prognosis remains challenging due to its complex molecular landscape, drug resistance, and high treatment costs. Recent research highlights the potential of natural compounds, particularly terpenes and terpenoids, derived from essential oils (EOs), to enhance NSCLC treatment. These compounds exhibit anticancer properties and modulate key pathways like the 4-oxo-retinoic acid pathway, TNF-α signaling, NF-κB activation, and histone deacetylases (HDACs). Retinoids, a subclass of terpenes, show both chemopreventive and therapeutic benefits, especially when combined with other agents, though challenges in dosing and delivery methods limit their clinical application. Terpenes may also synergize with emerging therapies, such as antiangiogenic treatments and immunotherapy, to improve outcomes. Biomarkers, including genomic, epigenomic, and proteomic markers, play a critical role in predicting responses to terpene-based treatments, supporting personalized medicine. The integration of terpenes into existing regimens, in combination with conventional therapies, holds promise in overcoming clinical challenges, improving patient outcomes, and advancing natural compound use in modern oncology. Future research should focus on optimizing terpene therapies and addressing clinical hurdles.

Humans↗
PubMed2025

HDAC inhibition unlocks tumor plasticity and enhances immunotherapy response in Myc-Driven Small Cell Lung Cancer.

Small Cell Lung Cancer (SCLC) is a highly aggressive malignancy, accounting for approximately 15% of all lung cancer cases. Characterized by low immunogenicity, SCLC may utilize epigenetic mechanisms to evade immune detection. Here, we demonstrate that entinostat, a class I histone deacetylase inhibitor (HDACi) upregulates immune-related genes in human SCLC cells. In vivo, we confirmed entinostat treatment increased expression of immunecheckpoint ligands and antigen presentation machinery in Myc-driven tumors in a Rb1/Trp53/MycT58A (RPM) SCLC mouse model, while shifting tumors from a neuroendocrine(NE)-high to a NE-low phenotype. Notably, combining entinostat with anti-PD-1 immunotherapy significantly enhances T-cell infiltration, suppresses tumor growth, and prolongs survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the immunological landscape and NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.

anti-PD-1 therapy↗