Histone deacetylase inhibitor

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Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced euchromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.

Contents

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, such as valproic acid. Since at least 2003 they have been investigated as possible treatments for cancers, [1] [2] parasitic [3] and inflammatory diseases. [4]

Cellular biochemistry/pharmacology

To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active euchromatin, and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression. [5] [6] [7] The open chromatin resulting from inhibition of histone deacetylases can result in either the up-regulation or the repression of genes. [7]

As of 2015, the histone deacetylase inhibitors were a "new" class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Histone deacetylase inhibitors exert their anti-tumour effects via the induction of expression changes of oncogenes or tumour suppressors through modulating the acetylation/deacetylation of histones and/or non-histone proteins such as transcription factors. [8] Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase inhibition induces the accumulation of hyperacetylated nucleosome core histones in most regions of chromatin but affects the expression of only a small subset of genes, leading to transcriptional activation of some genes, but repression of an equal or larger number of other genes. Non-histone proteins such as transcription factors are also targets for acetylation with varying functional effects. Acetylation enhances the activity of some transcription factors such as the tumor suppressor p53 and the erythroid differentiation factor GATA1 but may repress transcriptional activity of others including T cell factor and the co-activator ACTR. Recent studies [...] have shown that the estrogen receptor alpha (ERalpha) can be hyperacetylated in response to histone deacetylase inhibition, suppressing ligand sensitivity and regulating transcriptional activation by histone deacetylase inhibitors. [9] Conservation of the acetylated ER-alpha motif in other nuclear receptors suggests that acetylation may play an important regulatory role in diverse nuclear receptor signaling functions. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents." [10]

HDAC classification

Based on their homology of accessory domains to yeast histone deacetylases, the 18 known human histone deacetylases as of 2015 were classified into four groups (I-IV): [11]

HDI classification

The "classical" HDIs act exclusively on Class I, II and Class IV HDACs by binding to the zinc-containing catalytic domain of the HDACs. These classical HDIs can be classified into several groupings named according to the chemical moiety that binds to the zinc ion (except cyclic tetrapeptides which bind to the zinc ion with a thiol group). As of 2005, some examples in decreasing order of the typical zinc binding affinity were: [12]

  1. hydroxamic acids (or hydroxamates), such as trichostatin A,
  2. cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
  3. benzamides,
  4. electrophilic ketones, and
  5. the aliphatic acid compounds such as phenylbutyrate and valproic acid.

Asd of 2007, "second-generation" HDIs included the hydroxamic acids vorinostat (SAHA), belinostat (PXD101), resminostat, abexinostat, Givinostat, LAQ824, and panobinostat (LBH589); and the benzamides  : entinostat (MS-275), tacedinaline (CI994), zabadinostat, and mocetinostat (MGCD0103). [13] [14]

The sirtuin Class III HDACs are dependent on NAD+ and are, therefore, inhibited by nicotinamide, as well as derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphthaldehydes. [15]

Additional functions

HDIs should not be considered to act solely as enzyme inhibitors of HDACs. A large variety of nonhistone transcription factors and transcriptional co-regulators are known to be modified by acetylation. HDIs can alter the degree of acetylation nonhistone effector molecules and, therefore, increase or repress the transcription of genes by this mechanism. Examples include: ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, MKP-1, NF-κB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc. [12] [16] [17]

Uses

Psychiatry and neurology

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. As of 2008, HDIs were being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. [18] Enhancement of memory formation was increased in mice given vorinostat, or by genetic knockout of the HDAC2 gene in mice. [19] While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice with a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins. [20]

Preclinical research for the treatment of depression

2012 research into the causes of depression highlighted some possible gene-environment interactions that could explain why after much research, no specific genes or loci have emerged which would indicate risk for depression [21] 2016 studies estimate that even after successive treatments with multiple antidepressants, almost 35% of patients did not achieve remission, [22] suggesting that there could be an epigenetic component to depression which is not addressed by pharmacological treatments. Environmental stressors, namely traumatic stress in childhood such as maternal deprivation and early childhood abuse have been studied for their connection to a high risk of depression in adulthood. In animal models, these types of trauma have been shown to have significant effects on histone acetylation, particularly at gene loci which have known connection to behavior and mood regulation. [21] [23] 2011 research focused on the use of HDI therapy for depression after studies on depressed patients in the middle of a depressive episode found increased expression of HDAC2 and HDAC5 mRNA compared to controls and patients in remission. [23]

Effects on gene expression

As of 2011 various HDIs have been studied for their connection to the regulation of mood and behavior, each having different, specific effects on the regulation of various genes. The most commonly studied genes include Brain-derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) both of which help regulate neuron growth and health, whose down regulation can be a symptom of depression. [23] Multiple studies have shown that treatment with an HDI helps to upregulate expression of BDNF: valproic acid commonly used to treat epilepsy and bipolar disorder [22] as well as sodium butyrate [23] both increased expression of BDNF in animal models of depression. One study which traced GDNF levels in the ventral striatum found increased gene expression upon treatment with SAHA. [22]

Effects on depressive behaviors

Pre-clinical research on the use of HDIs to treat depression use rodents to model human depression. The tail suspension test (TST) and the forced swimming test (FST) measure the level of defeat in rodents— usually after treatment with chronic stress— which mirrors symptoms of human depression. Alongside tests for levels of HDAC mRNA, acetylation and gene expression these behavioral tests are compared to controls to determine whether or not treatment has been successful in ameliorating symptoms of depression. Studies which used SAHA or MS-275 found treated animals displayed gene expression profiles similar to those treated with fluoxetine, and displayed similar anti-depressant like behavior. [21] [22] [23] Sodium butyrate is commonly used as a candidate for mood disorder treatment: studies using it both alone and in co-treatment with fluoxetine report subjects with increased performance on both TST and FST [22] in addition to increased expression of BDNF. [23]

Cancer treatment

Pan-HDAC inhibitors have shown anticancer potential in several in in vitro and in vivo studies, focused on Pancreatic, Esophageal squamous cell carcinoma (ESCC), Multiple myeloma, Prostate carcinoma, Gastric cancer, Leukemia, breast, Liver cancer, ovarian cancer, non-Hodgkin lymphoma and Neuroblastoma. [24] Because of the massive effect of pan-HDAC inhibition, witnessed by the very low dosage concentration used and by the countless biological functions affected, many scientists have focused their attention on combining the less specific HDACi treatment with other more specific anti-cancer drugs, such as the efficacy of the combination treatment with the pan-HDAC inhibitor LBH589 (panobinostat) and the BET bromodomain JQ1 compound. [25]

Inflammatory diseases

Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents. [26]

HIV/AIDS

One study noted the use of panobinostat, entinostat, romidepsin, and vorinostat specifically for the purpose of reactivating latent HIV in order to diminish the reservoirs. Vorinostat was noted as the least potent of the HDAC inhibitors in this trial. [27] Another study found that romidepsin led to a higher and more sustained level of cell-associated HIV RNA reactivation than vorinostat in latently infected T-cells in vitro and ex vivo. [28]

Other diseases

Givinostat (ITF2357) is an orphan drug for treatment of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). Under the brand name Duvyzat "Givinostat" is used for the treatment of Duchenne muscular dystrophy. [29]

Myocardial Infarction

As of 2008, HDIs were also being studied as protection of heart muscle in acute myocardial infarction. [30]

Related Research Articles

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">Trichostatin A</span> Chemical compound

Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs. However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.

Vorinostat (rINN), also known as suberoylanilide hydroxamic acid, is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span> Biological processes used in gene regulation

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">HDAC6</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene. HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders.

<span class="mw-page-title-main">HDAC9</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.

<span class="mw-page-title-main">FOSB</span> Protein

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.

<span class="mw-page-title-main">Romidepsin</span> Chemical compound

Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene.

Cocaine addiction is the compulsive use of cocaine despite adverse consequences. It arises through epigenetic modification and transcriptional regulation of genes in the nucleus accumbens.

Embryonic stem cells are capable of self-renewing and differentiating to the desired fate depending on their position in the body. Stem cell homeostasis is maintained through epigenetic mechanisms that are highly dynamic in regulating the chromatin structure as well as specific gene transcription programs. Epigenetics has been used to refer to changes in gene expression, which are heritable through modifications not affecting the DNA sequence.

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

<span class="mw-page-title-main">Epigenetics of neurodegenerative diseases</span> Field of study

Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.

Epigenetics of depression is the study of how epigenetics contribute to depression.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.

H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.

<span class="mw-page-title-main">Epigenetic priming</span> Type of modification to a cells epigenome

Epigenetic priming is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons and tumor-suppressor gene activation in cancer treatment respectively.

Epigenetics of chronic pain is the study of how epigenetic modifications of genes affect the development and maintenance of chronic pain. Chromatin modifications have been found to affect neural function, such as synaptic plasticity and memory formation, which are important mechanisms of chronic pain. In 2019, 20% of adults dealt with chronic pain. Epigenetics can provide a new perspective on the biological mechanisms and potential treatments of chronic pain.

References

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