Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer's Disease.

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers.

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein of the leucine zipper family, which mitigates inflammation and employs cytoprotective effects. Attempting to unravel the epigenetic regulation of type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU), we profiled the expression of eleven isoform-specific histone deacetylases (HDACs) and correlated them with NRF2 and cytokines. This study recruited a total of 60 subjects and categorized into DFU patients (n = 20), T2DM patients (n = 20), and healthy controls (n = 20). The DFU patients were subcategorized into uninfected and infected DFU (n = 10 each). We observed a progressive decline in the expression of NRF2 and its downstream targets among T2DM and DFU subjects. The inflammatory markers IL-6 and TNF-α were significantly upregulated, whereas anti-inflammatory marker IL-10 was significantly downregulated in DFU. Of note, a significant upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2,8, SIRT1, SIRT2, SIRT3, SIRT7 among DFU patients were observed. The significant positive correlation between NRF2 and SIRT1 in DFU patients suggested the vital role of NRF2/SIRT1 in redox homeostasis and angiogenesis. In contrast, the significant negative correlation between NRF2 and HDAC1, 3 and 4, implied an imbalance in NRF2-HDAC1, 3, 4 circuit. Furthermore, a significant positive correlation was observed between HDAC4 and IL-6, and the negative correlation between SIRT1 and IL-6 suggested the pro-inflammatory role of HDAC4 and the anti-inflammatory role of SIRT1 in NRF2 signaling. In conclusion, the epigenetic changes such as upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2, 8, SIRT1, SIRT2, SIRT6, SIRT7 and their association with NRF2 as well as inflammatory markers are suggestive of their roles in pathophysiology of T2DM and DFU.

FpDep1, a component of Rpd3L histone deacetylase complex, is important for vegetative development, ROS accumulation, and pathogenesis in Fusarium pseudograminearum.

Histone deacetylases (HDACs) play essential roles in modulating chromatin structure to provide accessibility to gene regulators. Increasing evidence has linked HADCs to pathogenesis control in the filamentous plant fungi. However, its function remains unclear in Fusarium pseudograminearum, which has led to the emergence of the disease Fusarium crown rot in China. Here we identified the FpDEP1 gene, an orthologue of Saccharomyces cerevisiae DEP1 encoding a component of the Rpd3 histone deacetylase complex in F. pseudograminearum. The gene deletion mutant, ΔFpdep1, showed significantly retarded growth on PDA plates with reduced aerial hyphae formation. Pathogenicity tests displayed no typical leaf lesions and limited expansion capability of coleoptiles. Histopathological analysis indicated the ΔFpdep1 deletion mutant differentiated infectious hyphae and triggered massive reactive oxygen species (ROS) accumulation during the early infection stage, resulting in limited expansion to neighbor cells which was concurring with sensitivity to H2O2 and SDS tests in vitro. FM4-64 staining revealed that the ΔFpdep1 deletion mutant was delayed in endocytosis. The FpDEP1-GFP transgene complemented the mutant phenotypes and the fusion protein co-localized with DAPI staining, indicating that the FpDEP1 gene product is localized to the nucleus in spores and mycelia. Immunoprecipitation coupled with LC-MS/MS and yeast two-hybrid screening identified the Rpd3L-like HDAC complex containing at least FpDep1, FpSds3, FpSin3, FpRpd3, FpRxt3, FpCti6, FpRho23, and FpUme6. These results suggest that FpDep1 is involved in a HDAC complex functioning on fungal development and pathogenesis in F. pseudograminearum.

Beyond histone acetylation-writing and erasing histone acylations.

Histone post-translational modifications are crucial epigenetic mechanisms regulating a variety of biological events. Besides histone lysine acetylation, a repertoire of acylation types have been identified, including formylation, propionylation, butyrylation, crotonylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation, succinylation, malonylation, glutarylation and benzoylation. From a structural perspective, here we summarize the writers and erasers of histone acylations and explain the molecular basis of these enzymes catalyzing non-acetyl histone acylations with a focus on histone crotonylation and ß-hydroxybutyrylation. Histone acylation readout, non-histone acylations and metabolic regulation are also discussed in this review.

Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy.

Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomycetes origin, such as phenolics, polyketides, tetrapeptide, terpenoids, alkaloids, and hydoxamic acid, have been reported to show potential HDAC-inhibitory activity. Several HDACi of natural and dietary origin are butein, protocatechuic aldehyde, kaempferol (grapes, green tea, tomatoes, potatoes, and onions), resveratrol (grapes, red wine, blueberries and peanuts), sinapinic acid (wine and vinegar), diallyl disulfide (garlic), and zerumbone (ginger). HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells. This review summarizes the HDACs classification, their aberrant expression in cancerous tissue, structures, sources, and the anticancer mechanisms of HDACi, as well as HDACi that are either FDA-approved or under clinical trials.

HDAC genes play distinct and redundant roles in Cryptococcus neoformans virulence.

The human fungal pathogen Cryptococcus neoformans undergoes many phenotypic changes to promote its survival in specific ecological niches and inside the host. To explore the role of chromatin remodeling on the expression of virulence-related traits, we identified and deleted seven genes encoding predicted class I/II histone deacetylases (HDACs) in the C. neoformans genome. These studies demonstrated that individual HDACs control non-identical but overlapping cellular processes associated with virulence, including thermotolerance, capsule formation, melanin synthesis, protease activity and cell wall integrity. We also determined the HDAC genes necessary for C. neoformans survival during in vitro macrophage infection and in animal models of cryptococcosis. Our results identified the HDA1 HDAC gene as a central mediator controlling several cellular processes, including mating and virulence. Finally, a global gene expression profile comparing the hda1Δ mutant versus wild-type revealed altered transcription of specific genes associated with the most prominent virulence attributes in this fungal pathogen. This study directly correlates the effects of Class I/II HDAC-mediated chromatin remodeling on the marked phenotypic plasticity and virulence potential of this microorganism. Furthermore, our results provide insights into regulatory mechanisms involved in virulence gene expression that are likely shared with other microbial pathogens.

Genome-wide survey and phylogenetic analysis of histone acetyltransferases and histone deacetylases of Plasmodium falciparum.

Malaria parasites can readily sense and adapt to environmental changes, thus making the control and eradication of this disease difficult. Molecular studies have unraveled a very tightly coordinated transcriptional machinery governed by complex regulatory mechanisms including chromatin modification and spatiotemporal compartmentalization. Histone modifying enzymes play key roles in the regulation of chromatin modification and gene expression, which are associated with cell cycle progression, antigenic variation and immune evasion. Here, we present a comprehensive review of the key regulators of the Plasmodium falciparum histone acetylome; histone acetyltransferases (HATs); and histone deacetylases (HDACs). We describe the genome-wide occurrence of HATs and HDACs in the P. falciparum genome and identify novel, as well as previously unclassified HATs. We re-confirm the presence of five known HDACs and identify, a novel putative HDAC. Interestingly, we identify several HATs and HDACs with unique and noncanonical domain combinations indicating their involvement in other associated functions. Moreover, the phylogenetic analyses of HATs and HDACs suggest that many of them are close to the prokaryotic systems and thus potential candidates for drug development. Our review deciphers the phylogeny of HATs and HDACs of the malaria parasite, investigates their role in drug-resistance generation, and highlights their potential as therapeutic targets.

The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies.

Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors.

Lysine Deacetylase Inhibitors in Parasites: Past, Present, and Future Perspectives.

Current therapies for human parasite infections rely on a few drugs, most of which have severe side effects, and their helpfulness is being seriously compromised by the drug resistance problem. Globally, this is pushing discovery research of antiparasitic drugs toward new agents endowed with new mechanisms of action. By using a "drug repurposing" strategy, histone deacetylase inhibitors (HDACi), which are presently clinically approved for cancer use, are now under investigation for various parasite infections. Because parasitic Zn2+- and NAD+-dependent HDACs play crucial roles in the modulation of parasite gene expression and many of them are pro-survival for several parasites under various conditions, they are now emerging as novel potential antiparasitic targets. This Perspective summarizes the state of knowledge of HDACi (both class I/II HDACi and sirtuin inhibitors) targeted to the main human parasitic diseases (schistosomiasis, malaria, trypanosomiasis, leishmaniasis, and toxoplasmosis) and provides visions into the main issues that challenge their development as antiparasitic agents.

Diversity, evolution and expression profiles of histone acetyltransferases and deacetylases in oomycetes.

BACKGROUND: Oomycetes are a group of fungus-like eukaryotes with diverse microorganisms living in marine, freshwater and terrestrial environments. Many of them are important pathogens of plants and animals, causing severe economic losses. Based on previous study, gene expression in eukaryotic cells is regulated by epigenetic mechanisms such as DNA methylation and histone modification. However, little is known about epigenetic mechanisms of oomycetes. RESULTS: In this study, we investigated the candidate genes in regulating histone acetylation in oomycetes genomes through bioinformatics approaches and identified a group of diverse histone acetyltransferases (HATs) and histone deacetylases (HDACs), along with three putative novel HATs. Phylogenetic analyses suggested that most of these oomycetes HATs and HDACs derived from distinct evolutionary ancestors. Phylogenetic based analysis revealed the complex and distinct patterns of duplications and losses of HATs and HDACs in oomycetes. Moreover, gene expression analysis unveiled the specific expression patterns of the 33 HATs and 11 HDACs of Phytophthora infestans during the stages of development, infection and stress response. CONCLUSIONS: In this study, we reveal the structure, diversity and the phylogeny of HATs and HDACs of oomycetes. By analyzing the expression data, we provide an overview of the specific biological stages of these genes involved. Our datasets provide useful inputs to help explore the epigenetic mechanisms and the relationship between genomes and phenotypes of oomycetes.

Inhibition of histone deacetylases in melanoma-a perspective from bench to bedside.

Histone deacetylases (HDACs) are critically involved in epigenetic gene regulation through alterations of the chromatin status of DNA. Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer. Pharmacologic inhibition of HDACs shows potent antitumor activity in a panel of malignancies such as colon or gastric cancer and multiple myeloma. In this review, we summarize the current knowledge of HDACs in melanoma and evaluate the application of HDAC inhibition from an experimental and clinical perspective. The molecular functions of HDACs can be classified into histone and non-histone effects with diverse implications in proliferation, cell cycle progression and apoptosis. HDAC inhibition results in G1 cell cycle arrest, induces apoptosis and increases the immunogenicity of melanoma cells. Some studies proposed that HDAC inhibition may overcome the resistance of melanoma cells to BRAF inhibition. Several inhibitors such as vorinostat, entinostat and valproic acid have recently been tested in phase I and early phase II trials, yet most agents show limited efficacy and tolerability as single agents. The most frequent adverse events of HDAC inhibition comprise haematological toxicity, fatigue, nausea and laboratory abnormalities. Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition.

Regulation of class IIa HDAC activities: it is not only matter of subcellular localization.

In response to environmental cues, enzymes that influence the functions of proteins, through reversible post-translational modifications supervise the coordination of cell behavior like orchestral conductors. Class IIa histone deacetylases (HDACs) belong to this category. Even though in vertebrates these deacetylases have discarded the core enzymatic activity, class IIa HDACs can assemble into multiprotein complexes devoted to transcriptional reprogramming, including but not limited to epigenetic changes. Class IIa HDACs are subjected to variegated and interconnected layers of regulation, which reflect the wide range of biological responses under the scrutiny of this gene family. Here, we discuss about the key mechanisms that fine tune class IIa HDACs activities.

Non-sirtuin histone deacetylases in the control of cardiac aging.

Histone deacetylases (HDACs) catalyze the removal of acetyl-groups from lysine residues within nucelosomal histone tails and thousands of non-histone proteins. The 18 mammalian HDACs are grouped into four classes. Classes I, II and IV HDACs employ zinc as a co-factor for catalytic activity, while class III HDACs (also known as sirtuins) require NAD+ for enzymatic function. Small molecule inhibitors of zinc-dependent HDACs are efficacious in multiple pre-clinical models of pressure overload and ischemic cardiomyopathy, reducing pathological hypertrophy and fibrosis, and improving contractile function. Emerging data have revealed numerous mechanisms by which HDAC inhibitors benefit the heart, including suppression of oxidative stress and inflammation, inhibition of MAP kinase signaling, and enhancement of cardiac protein aggregate clearance and autophagic flux. Here, we summarize recent findings with zinc-dependent HDACs and HDAC inhibitors in the heart, focusing on newly described functions for distinct HDAC isoforms (e.g. HDAC2, HDAC3 and HDAC6). Potential for pharmacological HDAC inhibition as a means of treating age-related cardiac dysfunction is also discussed. This article is part of a Special Issue entitled: CV Aging.

Deacetylation of chromatin and gene expression regulation: a new target for epigenetic therapy.

Besides the genetic information thath is encoded by DNA, heritable information can also be passed on without relying on changes in the nucleotide sequence of DNA, a phenomenon known as epigenetics. Gene expression in eukaryotes is partly regulated by epigenetic mechanisms both at the DNA and histone protein levels. Chromatin structure can be influenced by various modifications, including the reversible posttranslational processes of acetylation and deacetylation of DNA-binding proteins. Histone acetyl transferase (HAT) is referred to as the writer of this process, whereas histone deacetylase (HDAC) is the eraser of this lysine modification. Dysregulation of gene expression and changes in the HDAC expression profile have been associated with carcinogenesis, and HDAC inhibitors are already approved for the treatment of cutaneous T-cell lymphoma and peripheral T-cell lymphoma. These inhibitors are able to influence epigenetic processes by targeting HDAC activity, increasing nuclear histone acetylation status, and contributing to chromatin remodeling, thereby affecting gene expression. In addition, HDACs also act on a plethora of cytosolic proteins with many cellular functions, including angiogenesis, immune responses, and autophagy. In this review, we will give an overview of histone deacetylase and how it can regulate gene expression at the chromatin level.

Modulation of immune responses by histone deacetylase inhibitors.

Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases.

Histone deacetylase inhibitors in hematological malignancies and solid tumors.

Histone deacetylase (HDAC) inhibitors are emerging as promising anticancer drugs. Because aberrant activity and expression of HDACs have been implicated in various cancer types, a wide range of HDAC inhibitors are being investigated as anticancer agents. Furthermore, due to the demonstrable anticancer activity in both in vitro and in vivo studies, numerous HDAC inhibitors have undergone a rapid phase of clinical development in various cancer types, either as a monotherapy or in combination with other anticancer agents. Although preclinical trials show that HDAC inhibitors have a variety of biological effects across multiple pathways, including regulation of gene expression, inducing apoptosis and cell cycle arrest, inhibiting angiogenesis, and regulation of DNA damage and repair, the mechanism by which the clinical activity is mediated remains unclear. Understanding the mechanisms of anticancer activity of HDAC inhibitors is essential not only for rational drug design for targeted therapies, but for the design of optimized clinical protocols. This paper describes the links between HDACs and cancer, and the underlying mechanisms of action of HDAC inhibitors against hematological malignancies and solid tumors. Further, this review presents the clinical outcomes of vorinostat, romidepsin, and belinostat, which are approved by the United States Food and Drug Administration for the treatment of lymphomas.

Targeting Histone Deacetylases in Diseases: Where Are We?

SIGNIFICANCE: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. RECENT ADVANCES: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. CRITICAL ISSUES: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. FUTURE DIRECTIONS: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment.

Epigenetic therapy of cancer with histone deacetylase inhibitors.

Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III HDAC and Class IV (HDAC11). Histone Deacetylase Inhibitors (HDACI) exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates. The effects of HDACI on gene transcription are complex. They cause cell cycle arrest, inhibit DNA repair, induce apoptosis and acetylate non histone proteins causing downstream alterations in gene expression. HDACI are a diverse group of compounds, which vary in structure, biological activity, and specificity. In general, HDACIs contain a zinc-binding domain, a capping group, and a straight chain linker connecting the two. They are classified into four classes namely short chain fatty acids, hydroxamic acids, cyclic peptides and synthetic benzamides. This review describes the clinical utility of HDACI as monotherapy as well as combination therapy with other treatment modalities such as chemotherapy and radiotherapy. Adverse effects and shortcomings of treatment with HDACI are also discussed in detail.

Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.

Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.

Erasers of histone acetylation: the histone deacetylase enzymes.

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.