- Email: [email protected]
Role of HDAC inhibitors in diabetes mellitus
G Model RETRAM 3233 No. of Pages 6
Current Research in Translational Medicine xxx (2019) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
General review
Role of HDAC inhibitors in diabetes mellitus Rashita Makkara , Tapan Behla,* , Sandeep Arorab a b
Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India Department of Pharmacy, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 April 2019 Accepted 21 August 2019 Available online xxx
Objective: The role of histone deacetylases has come out as an emerging remedy in control and treatment of various metabolic disorders and cancers. This review highlights their intricate role in diabetes mellitus as well as its associated complications. Key findings: Through recent studies and reports the role of various epigenetic markers in treatment of diabetes mellitus has been revealed. HDAC enzyme regulates the structure of chromatin and transcripts genes in the nucleus synthesizing various proteins that control metabolic activities in the body. It mainly acts by removing an acetyl group from its precursor protein thereby modulating gene expression and regulates the metabolic enzyme acetylation in mitochondria and cytosol. Summary: The present review focus on the intrinsic role of HDAC inhibitors as an emerging remedy for diabetes and its complications demonstrating their use in preventing resistance of β-cells towards insulin, destruction of β-cells and provide protection against cytokine mediated attack on pancreatic cells. © 2019 Elsevier Masson SAS. All rights reserved.
Keywords: Histone deacetylases Insulin resistance Acetylation Transcription β-cell destruction Gene expression
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . Diabetes mellitus . . . . . . . . . . . . . . . . . . Role of HDACs in etiology of diabetes . . HDAC inhibitors and insulin signaling . HDAC inhibitors and activity of β-CELLS HDACs as treatment approach . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . Declaration of Competing Interest . . . . References . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
Introduction Diabetes mellitus allocates a group of chronic diseases where aberrancies in substrate metabolism occur in response to relative or absolute lack of insulin with pronounced long term complications. The disease may be due to inherited or acquired deficiency of insulin synthesis or its inability to bind to receptor and produce effective results. Various body systems particularly the nerves and blood are highly damaged due to increased levels of glucose
* Corresponding author. E-mail addresses: [email protected], [email protected] (T. Behl) .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
00 00 00 00 00 00 00 00 00
making it an essential hallmark of the disease [1]. The WHO last reported the prevalence of diabetes in October 2018 [2]. The number of people affected with the disease has reached to 422 million from 108 million in 1980 and the numbers are supposed to double every ten years. The prevalence of disease has also reached upto 8.5% from 4.7% among the individuals above 18 years in 1980. The low and middle income countries are more exposed to diabetes and it has become one of the major causes of blindness, stroke, lower limb amputations, kidney failure and heart attacks. Diabetes has also been stamped to be the 7th leading cause of death in 2016 by WHO [3,4]. The long recognized causes of type I diabetes include destruction of β-cell and autoimmune islet inflammation though it is still debated whether molecular mechanisms involve predominantly inflammatory cytokine
http://dx.doi.org/10.1016/j.retram.2019.08.001 2452-3186/© 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
2
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
mediated β-cell destruction or classical cytotoxic T-cell mediated killing or both. A number of mechanisms explaining destruction of β-cells have been proposed like glucolipotoxicity, islet amyloid polypeptide deposition mediated disruption of membrane and inflammation of islets. Later, a unified hypothesis was proposed that explained the cause of β-cell destruction by induction of inflammatory mediators in pancreatic islets that further activate pathways in β-cells resembling those in type 1 diabetes (T1D) [5,6]. The inventory processes for developing novel treatment approaches has undergone a revolutionary turn which has aided study and targeting of newer protein molecules with exceptional outcomes. A drug developer is no less than an artist as targeting specific proteins with respect to disease pathology to achieve higher degree of effective treatment with minimal possible side effects is not a job of left hand. The recent trend of drug development has turned to epigenetic modifications in gene expressions of the diseased patient which aims at targeting proteins involved in pathogenesis of the disease. The manner in which DNA is packaged profoundly influences the transcription of genes in eukaryotic cells. The stable and potentially reversible alteration in gene expressions of an individual without any permanent change in DNA sequence with inheritance property is called epigenetic modifications [7]. Waddington originally defined epigenetics as a firm reason for programmed changes during development of embryo due to interactions between genes and their products bringing out a phenotypic change. The bridge between environment and genetics is epigenome while determining the final phenotype on modification of gene expressions without any alteration in DNA sequence is epigenetic code. By targeting the specific gene directly, the phenotype of the disease can be changed through epigenetic modifications in response to pathological and environmental conditions like diet, exercise, toxins, inflammation, oxidative stress and metabolic changes. The epigenetic modifications show a phenomenal role in genomic imprinting, stable inheritance of gene expression, embryonic development, cell differentiation and identity, inactivation of X chromosome, immune cell functioning, and responses to environmental signals at cellular levels [8]. One such emerging epigenetic modification that is being investigated recently is Histone modification. It has managed to obtain exceptional results in treatment of severe life threatening diseases including cancer and metabolic disorders [9]. Gene transcription processes in cells of eukaryotes depend highly upon the chromatin confirmation. Nucleosome is the basic unit of chromatin constituting four core dimers of histones namely H2A, H2B, H3 and H4 which are doubly folded around the DNA in the form of an octamer. The covalent modifications undergo in the basic N-terminal tail of histone proteins which recruit factors responsible for transcription via changes in structure causing packaging of chromatin and regulate gene expression [10]. The remodeling of chromatin through acetylation, phosphorylation, methylation and various other posttranslational modifications in histones is the fundamental phenomenon in eukaryotic cell biology highlighting diverse approaches for treatment in response to physiological and pathological conditions. The histone acetyl transferase (HAT) and histone deacetylase (HDAC) as their name suggests acetylate and deacetylate histone proteins respectively [11,12]. The HAT enzyme undergoes posttranslational histone acetylation by transferring an acetyl group from acetyl coenzyme A to the e-NH3 groups of internal residues of histone proteins. Acetylation forms decondensed chromatin called ‘euchromatin’ by neutralizing the positive charge on tail of N-terminal residues of lysine. This decreases the propensity of positive terminal residues towards DNA activation, increasing access of DNA towards transcription factors and RNA polymerase by unfolding nucleosomes and causes gene activation. In contrast to HAT, the enzyme HDAC acts by
removing acetyl group from histone lysine residues and restores the persisting positive charge on terminal tails of Nitrogen therefore increasing their likeliness for DNA. The tails displace transcription factors and forms a repressive structure of chromatin hence suppress transcription [13]. The mammalian HDACs can be divided into two families and four classes. The first family includes category of HDACs that are classically Zinc ion dependent while the other family is nicotinamide adenine dinucleotide (NAD) dependent HDACs. The Zn dependent family of HDACs includes: Class I HDACs: It comprises of HDAC isoforms 1, 2, 3 and 8. These HDACs are localized and found exclusively in the nucleus and are related to Rpd3 yeast enzyme with homology shared in catalytic pocket. Class II HDACs: It is advanced into two categories which is Class IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10). It covers two homology regions, in Nitrogen terminal regulatory area and Carbon terminal area of catalysis. The HDACs circulate between nucleus and cytosol with certain recruitment of protein complexes and deacetylation sites occur. Class IV HDACs: They comprise only one member i.e. HDAC 11. It is found in both nucleus as well as cytoplasm. The NAD+ dependent family of HDACs include: Class III HDACs: They are also called the silent information regulator 2. The HDAC enzymes are dependent on NAD+ under presence of which acetyl groups are removed from residues of acetylated lysine. This class includes homology of yeast Sir 2, which in presence of cofactor NAD acts as a vital protein for silencing certain genes and catalyze their action. They are also called Sirtuins. Till now seven members have been noted in the family of protein sirtuin localized in mitochondria, nucleus and cytoplasm of the cell [14]. The deacetylation action of HDAC 6 is higher on 5th and 8th lysine residue of histone 4 while HDAC 1 and 3 have been tested for their efficacy to deacetylate the lysine residues containing four core histones on varied levels [15,16] (Table 1). HDAC inhibitors through hyperacetylation of non histone and nucleosomal histone proteins regulate expression of genes. Most of the HDACs are large multiprotein complex regulated and do not activate enzymatically without interacting with other proteins. NuRD/Mi2, coREST, Sin3, and N-CoR and SMRT, the nuclear receptor corepressors are some of the multiprotein complexes required in the activation of HDAC proteins. The SMRT and N-coR nuclear receptor complexes enzymatically activate HDAC3 whereas the other complexes i.e. the Sin 3, CoREST and NuRD/Mi2 complexes stimulate the activity of HDAC1and HDAC2 deacetylase. Class IIa HDACs recruit HDAC3 comprising N-CoR/SMRT active complexes and are inactive HDACs. HDACs and its inhibitors predominantly control cell proliferation, differentiation, apoptosis and also modulate cell cycle by regulating cellular reactions [17,18]. HDACs have multiple actions as they target numerous cellular pathways and produce resultant responses. HDACs bind to nuclear receptors and regulate signaling of hormones by modulating their release. This indicates its use in management of diabetes mellitus as HADCs stimulate release of insulin. The α-tubulin proteins are expressed in the cytosol of the cells. HDAC 6 is highly specific and binds to α-tubulin and actin proteins which control the stability and functioning of microtubules. The acetylation state of actin is highly modulated by HDAC6 thereby blocking its fibrillar action and affects actin dependent motility. Angiogenesis is also prevented by use of HDAC inhibitors as angiogenic markers like VEGF and HIF-1α are targeted by HDACs The role of HDACs in modulating inflammation by suppressing outburst of inflammatory mediators has already been discussed in the article.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
3
Table 1 An overview of HDACs. CLASS
NAME
LOCATION
Co - FACTOR
EXPRESSING TISSUES
USES
CLASS I
HDAC 1 HDAC 2 HDAC 3 HDAC 8 HDAC 4 HDAC 5 HDAC 7 HDAC 9 HDAC 6 HDAC 10 SIRT 1 SIRT 2 SIRT 3 SIRT 4 SIRT 5 SIRT 6 SIRT 7 HDAC 11
Nucleus
Zn2+ DEPENDENT
Widespread
Inflammation, Insulin resistance
Heart, Brain Smooth muscle Placenta, Pancreas, Heart Smooth muscle, Brain Kidney, Liver, Heart Spleen, Kidney, Liver White adipose tissue Testes, Heart, Brain Brown adipose tissue Islets of pancreas Liver
Hyperglycemia, Insulin resistance, Decreased insulin production
CLASS II (a)
CLASS II (b) CLASS III
CLASS IV
Nucleus/Cytoplasm Nucleus Nucleus/Cytoplasm
Nucleus, Cytoplasm Cytoplasm Mitochondria
+
NAD DEPENDENT
Nucleus Nucleus
Zn2+ DEPENDENT
HDACs suppress tumor growth by binding to p53, p21 and cyclin proteins and alter cell cycle of the body. Diabetes mellitus The main source of energy for most of the cellular functions is glucose. An increased level of circulating glucose in body post meal stimulates pancreatic β cells to release insulin. Insulin plays an important role in glucose homeostasis. It undergoes autophosphorylation on binding with transmembrane receptors and phosphorylates the intercellular protein substrates including insulin receptor substrate – 1 and 2 (IRS-1 and IRS- 2). The phosphorylated IRS subsequently activates phosphoinositide 3kinase (PI3K/AKT) pathway. These phosphorylated products stimulate activation of several enzymes and proteins and translocate glucose transporter 4 (GLUT 4) to cell membrane from intracellular cell vesicles. An array of metabolic events is demonstrated by another important pathway in insulin signaling called mitogen activated protein kinase (MAPK) pathway [19]. Over the last century drastic behavioural and lifestyle changes have produced conditions of insulin resistance where amidst the presence of abundant amount of insulin, it is no longer able to bind to its receptor causing prohibition of any further series of events [20]. Diabetes can be categorized into two principal forms: Type I diabetes: formerly known as insulin dependent diabetes, is a condition where pancreas fails to synthesize insulin hence disturbing homeostasis of glucose in body. It is frequently observed in children and adolescents and is termed juvenile diabetes. Type II diabetes: also known as non-insulin dependent diabetes, is a condition in which the body fails to respond to pre-existing insulin. About 90% of diabetic cases worldwide are accounted to be T2D and predominantly targets adults [21]. Mutations in one or more genes by genetic-environmental interactions trigger onset of diabetes making it a complex disease. Both the types of diabetes are genetically distinct where type I diabetes is believed to happen due to variations in immune regulatory genes highlighting its autoimmune nature and exposing individuals to T-cells driven β-cell destruction and chronic inflammation whereas in contrast genome wide association scans (GWAS) suggested type II diabetes as a disease where alterations in genes evoke changes on β-cell function and impairs its compensation to increased demands of insulin [1]. The immune and metabolic pathogenesis of both types of diabetes seems to
Heart, Smooth muscle, Brain, Kidney
Glucose intolerance, Hyperglycemia Enhanced insulin signaling Impaired insulin signaling Enhanced insulin signaling Impaired insulin signaling Enhanced insulin signaling Impaired insulin signaling Enhanced insulin signaling Inflammation
converge on common extracellular inflammatory stressors despite their dissimilar genetic background and these stressors induce intracellular signaling in islet cells. The most commonly reported intracellular stressors is IL-1β which is secreted from activated mononuclear cells that prohibit functioning of β-cell and cause cell death on prolonged exposure due to their selective β-cell toxicity [22,23]. The molecular performance of HDAC was assumed to be limited to deacetylation as indicated by their name but recent advances in phylogenetic analysis suggested their role in regulating performance in a broader range of non histone proteins. In terms of posttranslational mechanisms the impact of acetylation is no less than phosphorylation increasing demand of HDACi as a treatment approach for an expanding range of diseases. The original goal of HDAC inhibition was transcriptional control over oncogene networks in cancer cells but their indications as novel treatment in other diseases including neurodegenerative and inflammatory diseases is growing exceptionally. The master transcription factor nuclear factor (NF-kB) in inflammation is now recognized to be regulated by acetylation. In the current review the prospects of inhibition of HDAC as a novel approach for treatment of diabetes will be reviewed. It also incorporates an outline of genetic associations relating to etiology of diabetes and HDACs and evaluating its potential as an oral therapy in treatment of disease and its associated complications depending upon the pathological events [24,25]. Role of HDACs in etiology of diabetes A combination of environmental and genetics factors contribute in the etiology of diabetes making it complex. Though T1D and T2D are considered to be genetically distinct, an association between the 6q21 chromosomal region has been identified by genome wide association scans (GWAS) studies where HDAC 2 is also located signifying the latter’s role in both the diabetes. The epigenetic and environmental factors significantly contribute in the etiology of the disease making it a polygenetic disorder. Simmons and Pinney reported that an unfavorable fetal milieu due to exposure of fetus to intra uterine growth retardation (IUGR) affects the development of β-cells due to modification in muscular transport of glucose by glucose transporter 4 (GLUT 4) and varying key regulatory genes like pancreatic and duodenal homeobox factor 1 (Pdx1) thereby advancing to T2D. Loss of acetylation of histone recruits HDAC1 which complexes Pdx1 a proximal
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
4
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
promoter to the Sin3A corepressor hence reducing the expression of Pdx1after IUGR. The HDAC1/Sin3 complex formed propagates epigenetic cycle and recruits histone demethylase which inhibits the transcription of Pdx1 thereby causing loss of histone 3 lysine 4 trimethylation (H3K4me3). Inhibition of HDACs reverses this effect by methylation and dimethylation of H3K9 which lodges the promoter Pdx1 in its transcriptionally inactive state [26]. The transcription of Glut4 is inhibited as a result of lack of histone acetylation in adult muscle tissue of Glut 4 promoter as mediated by HDAC1 and HDAC4 thereby repressing the peripheral uptake of glucose and producing insulin resistance thus contributing to T2D. The remodeling of chromatin in incretin hormones such as glucose dependent insulinotropic peptide 1 and glucagon-like peptide 1 has already been induced as a therapeutic approach in treatment of T2D which has led to greater association with the transcription factors due to in vitro global acetylation of H3 histones [27,28]. HDACs and histone acetylation are also useful in treatment of rare kinds of autosomal diabetes namely “maturity onset diabetes of the young” (MODY) and its seven dissimilar subtypes based on the mutations in genes apart from their clinical relevance in treatment of T1D and T2D. The genes encode nearly all transcription factors which are involved in the production of insulin and development of pancreas except for insulin and glucokinase. Some of these include hepatocyte nuclear factor (HNF)- 1α, -1β and -4α which produces hepatic gluconeogenesis and transcription of insulin, neurogenic differentiation 1 (NeuroD1) and Pdx1. Histone acetyl transferases (HATs) and HDACs by remodeling chromatin interact with the transcription factors and regulate normal functioning suggesting their important role in pathogenesis of diabetes [29]. HDAC inhibitors and insulin signaling The signaling of insulin is vital in maintaining the glucose homeostasis in body as a decline in its signaling inhibits hepatic steatosis in liver and containment of gluconeogenesis with reduced uptake of glucose in muscles. Insulin signaling also regulates the mass of β-cells which is directly involved in onset and progression of diabetes [30]. The Fig. 1 below describes the pathway for insulin signaling. On binding to insulin receptor, the autophosphorylation and phosphorylation of insulin receptor substrate (IRS) family members occurs causing release and action of insulin. The IRS proteins post phosphorylation bind and activate phosphatidylinositol 3-kinase which further stimulate protein kinase Akt phosphorylation ultimately translocating glucose transporter (GLUT 4) to the plasma membrane from intracellular vesicles and mediating uptake of glucose. The myocyte enhancer factor (MEF)-2 and GLUT 4 enhancer factor (GEF) are chief
regulators that control translocation of GLUT 4 by binding to its translational elements [31]. The obstruction in release of insulin may occur at several stages. There are two mechanisms that control the signaling of insulin in β-cells through HDACs, firstly through epigenetic control while secondly through IRS2 expression and activity regulation via protein acetylation [32]. The role of IRS2 has been reported to be very crucial in proliferation of β-cells of pancreas hence identifying and employing a precise isoform of HDAC can be a valuable approach as therapy forT2D [33]. The HDAC1 located in nucleus acts via acetylation of histone in the promoter region of IRS2 while the cytoplasm localized HDAC acetylates the lysine residues in IRS2 and leads to modification of proteins [34]. The expression of different isoforms of HDACs differed in the brain with altered activity in kidneys of diabetic patients. The differentiation of β-cells of pancreas was reported to be controlled by HDAC 4, 5 and 9. An increased expression of HDAC1 was encountered from pancreatic cells isolated from children with T1D with decrease in HDAC2 and HDAC3 expressions. The secretion of insulin is suppressed by histone acetylation and promoted expression of Tcf7l2 with increased articulation of HDAC7 in pancreatic cells of T2D patients. The acetylation of lysine in SREBP 1a and p53 inhibits ubiquitination while acetylation of lysine in PGC1α and FOXO promotes autophosphorylation. The phosphorylation of tyrosine in neuronal cells seems to diminish on IRS2 post translational modification due to acetylation of lysine in IRS2 with no reports β cells of pancreas [35,36]. The patients receiving HDAC inhibitors as therapy for treatment of cancer have been reported to fabricate hyperglycemia as its consequence indicating its role in signaling of insulin in some organs with impairment of tolerance to glucose. Hence through these findings the need to pick more selective HDAC inhibitors can be suggested necessary to provide protective effect for insulin signaling [37,1] (Fig. 2). HDAC inhibitors and activity of β-CELLS The factors mediating transcription play crucial role in development of pancreas by differentiation of endocrine and exocrine. The etiology of type-1 diabetes is highlighted by the understanding of mechanism of apoptosis of β-cells induced by inflammatory cytokines. The molecules with capability to suppress this apoptotic processes can be efficiently employed as therapy for preventing β-cells from hypersensitive reactions and immune responses. Various studies have reported the protective actions of HDAC inhibitors in preventing destruction of β-cells [38]. The determination of precise isoform of HDAC which is responsible for survival of β-cells is fundamental to its therapeutic application as
Fig. 1. signaling pathways associated with HDACs.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
5
proteins accumulate on HDACi treatment modifying their functions [41,42]. The targets in pancreas that can are involved in etiology of DM are also under investigation for contributing better in expression and regulation of Ngn3. Hence through various studies the role of HDACs in proliferation of β-cells has been stated evident as they have direct effects on fate regulation of endocrine cells [1] (Fig. 3). HDACs as treatment approach
Fig. 2. Mechanism of Insulin Signaling.
broad spectrum HDAC inhibitors may have toxic effects and fail to restore significant β-cell functions like secretion of insulin as stimulated by levels of glucose [39]. Genetic and chemical inhibition of HDAC3 has been found to suppress the apoptosis of β-cell line of rats. The selective HDAC 1, 2 and 3 inhibitors embarked better protective effects in β-cell line as compared to broad spectrum HDAC inhibitors like SAHA indicating additional side toxicities induced by inhibition of various isoforms of HDAC. MS-275 a selective HDAC inhibitor he genetic knock down of HDAC3 stimulated secretion of insulin in response to glucose levels and restores it [40]. The development of endocrine progenitors of NGN3+ was enhanced on treatment with HDACi. The epithelial cells in pancreas contain precursors for PDX1+ which augments development of various cell types of pancreas besides NGN3+ cells. On enhancing proliferation of precursors of PDX1+ by FGF 10 or mesenchyme the progenitors of endocrine NGN3+ are intensified. On initiating treatment with HDACi no increase in the production of PDX1+ precursors was noticed indicating role of HDACi and FGF 10 in enhancing the endocrine progenitors NGN3+ in alternate ways except for poorly growing cells of NGN3+ making it independent of proliferation of cells. Also the relationship between the β-cell signaling of transforming growth factor in differentiation of pancreatic cells is being investigated. A possibility of HDACi to inhibit the promoter NGN3+ cells directly as mechanism of action is being explored for its therapeutic efficiency. The presence of non histone substrates of proteins in HDACi regulates expression of genes and also controls death and proliferation of cells. The acetylated forms of these substrate
Various HDACi have recently been approved by FDA e.g., Panobinostat is under phase IV clinical trials and has also been approved by FDA in 2015 for its use in management of multiple myeloma and cutaneous T-cell lymphoma (CTCL) Some of the HDACi under clinical trials include: Valproic acid is under phase III clinical trials for its use in cervical and ovarian cancer. Tacedinaline, another HDACi is under phase III trials for its use in management of multiple myeloma and lung cancer. Mocetinostat is under phase II clinical trials for its use in management of Follicular and Hodgkin lymphoma and acute myeloid leukemia. Rocilinostat has been recently developed and is under phase I trials for its use in treatment of multiple myelomas. Many other HDAC inhibitors drugs like Mocetinostat, Abexinostat, Practinostat are under phase II clinical trials and are being studied for their beneficial effects in treatment of Follicular and Hodgkin lymphoma and acute myeloid leukemia, Sarcoma and lymphoma and Recurrent or metastatic prostate cancer respectively. Some of the HDACs used in management of diabetes mellitus include: Vorinostat (SAHA) was the first HDAC inhibitor to be approved by FDA in 2006 for its use in treatment of cutaneous T-cell lymphoma. Apart from its use in myeloma, SAHA is also being examined for its therapeutic role in management of diabetes mellitus as its is reported to increase expression of insulin even in low concentrations of glucose. Sodium butyrate (NaB) and Trichostatin A (TSA) are other HDACi that are simultaneously being examined for their use in diabetes mellitus. TSA is believed to increase insulin release by stimulating expression of β-cells and stimulating GLP-1 proteins. TSA also improved the transdifferentiation of bone marrow stem cells into insulin-producing cells Sodium butyrate (NaB) stimulates early events of pancreatic specification in embryonic stem (ES) cells by promoting their differentiation into insulin-producing cells. Valproate has been used commonly in treatment of bipolar disorders and other CNS disorders. A typical side effect associated with Valproate was hyperinsulinemia. It was found that the function is attributed to inhibition of HDACs by Valproate. Hence,
Fig. 3. HDAC inhibitors and β-cell destruction.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
6
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
valproate is also under study for evaluation of its effect in management of diabetes mellitus. Various other HDACi like Romidepsin, Panabiostat have been approved by FDA for management of lymphomas and their role in diabetes is yet under investigation. Conclusion HDACs are indulged in multiple biological system pathways and contribute majorly in pathogenesis and development of diabetes mellitus even through genetic basis. HDACs promote development, proliferation and differentiation of β-cells and regulate their functioning by preventing inflammatory cell damage, improve resistance of insulin and prevent microvascular complication of diabetes at later stages. Altogether it can be summoned that HDACi can be initiated as promising therapy for preventing and treating diabetes and its clinical utility is under examination as there is still a lot to be learned about its mechanism. Declaration of Competing Interest The author(s) declare no conflict of interest. References [1] Christensen DP, Dahllöf M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N, et al. T. HDAC inhibition as a novel treatment for diabetes mellitus. 2011. [2] Kaiser AB, Zhang N, Van der Pluijm W. Global prevalence of type 2 diabetes over the next ten years (2018–2028). 2019. [3] Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus: present and future perspectives. Nat Rev Endocrinol 2014. [4] Frier BM. Hypoglycaemia in diabetes mellitusA and clinical implications. Nat Rev Endocrinol 2014;10(12):711. [5] Adeghate E, Schattner P, Dunn E. An update on the etiology and epidemiology of diabetes mellitus. Ann N Y Acad Sci 2006;1084(1):1–29. [6] Alonso-Magdalena P, Quesada I, Nadal A. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol 2011;7(6):346. [7] Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010;28(10):1057. [8] Kanwal R, Gupta S. Epigenetic modifications in cancer. Clin Genet 2012;81 (4):303–11. [9] Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol 2010;28(10):1069. [10] Abel T, Zukin RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 2008;8(1):57–64. [11] Shen Y, Wei W, Zhou DX. Histone acetylation enzymes coordinate metabolism and gene expression. Trends Plant Sci 2015;20(10):614–21. [12] Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet 2016;17:487–500. [13] Schütz LF, Park MH, Choudhury M. HDACs in diabetes: a new era of epigenetic drug. Nutritional and therapeutic interventions for diabetes and metabolic syndrome. second edition . p. 475–86. [14] Yang XJ, Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 2007;26:5310–8. [15] Sengupta N, Seto E. Regulation of histone deacetylase activities. J Cell Biochem 2004;93:57–67. [16] Kelly RD, Cowley SM. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem Soc Trans 2013;41:741–9. [17] Mathias RA, Guise AJ, Cristea IM. Post-translational modifications regulate class IIa histone deacetylase (HDAC) function in health and disease. Mol Cell Proteomics 2015;14:456–70.
[18] Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997;389:349–52. [19] Sharma S, Taliyan R. Histone deacetylase inhibitors: future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res 2016;113:320–6. [20] Ye J. Improving insulin sensitivity with HDAC inhibitor. Diabetes 2013;62:685–7. [21] Baynes HW. Classification, pathophysiology, diagnosis and management of diabetes mellitus. J Diabetes Metab 2015;6(5):1–9. [22] DMICC. Genetic basis of type 1 and type2 diabetes, obesity, and their complications. Advances and emerging opportunities in diabetes research: a Strategic Planning report of the DMICC. 2014. [23] Pablo A. Recent advances in understanding/managing type 2 diabetes mellitus. F1000Research 2017;6. [24] Sharma S, Taliyan R. Histone deacetylase inhibitors: future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res 2016;113:320–6. [25] Gray SG, De Meyts P. Role of histone and transcription factor acetylation in diabetes pathogenesis. Diabetes Metab Res Rev 2005;21:416–33. [26] Pirola L, Balcerczyk A, Okabe J, El-Osta A. Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol 2010;6(12):665. [27] Sathishkumar C, Prabu P, Balakumar M, Lenin R, Prabhu D, Anjana RM, et al. Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics 2016;8(1):125. [28] Patel MM, Patel BM. Repurposing of sodium valproate in colon cancer associated with diabetes mellitus: role of HDAC inhibition. Eur J Pharm Sci 2018;121:188–99. [29] Hull EE, Montgomery MR, Leyva KJ. HDAC inhibitors as epigenetic regulators of the immune system: impacts on cancer therapy and inflammatory diseases. Biomed Res Int 2016. [30] Rafehi H, Kaspi A, Ziemann M, Okabe J, Karagiannis TC, El-Osta A. Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes. Epigenetics 2017;12(11):991–1003. [31] Anuradha R, Saraswati M, Kumar KG, Rani SH. Apoptosis of beta cells in diabetes mellitus. DNA Cell Biol 2014;33(11):743–8. [32] Remsberg JR, Ediger BN, Ho WY, Damle M, Li Z, Teng C, et al. Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion. Mol Metab 2017;6(1):30–7. [33] Khan S, Jena G. Valproic acid improves glucose homeostasis by increasing beta-cell proliferation, function, and reducing its apoptosis through HDAC inhibition in juvenile diabetic rat. J Biochem Mol Toxicol 2016;30(9):438–46. [34] McGee-Lawrence ME, Pierce JL, Yu K, Culpepper NR, Bradley EW, Westendorf JJ. Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity. J Cell Physiol 2018;233(4):2671–80. [35] Lundh M, Galbo T, Poulsen SS, Mandrup-Poulsen T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes Metab 2015;17(7):703–7. [36] Kawada Y, Asahara SI, Sugiura Y, Sato A, Furubayashi A, Kawamura M, et al. Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells. PLoS One 2017;12(9)e0184435. [37] Sun C, Zhou J. Trichostatin A improves insulin stimulated glucose utilization and insulin signaling transduction through the repression of HDAC2. Biochem Pharmacol 2008;76(1):120–7. [38] Sabir S, Saleem A, Akhtar MF, Saleem M, Raza M. Increasing beta cell mass to treat diabetes mellitus. Adv Clin Exp Med 2018. [39] Larsen L, Tonnesen M, Ronn SG, Størling J, Jørgensen S, Mascagni P, et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia 2007;50(4):779–89. [40] Vestergaard AL, Bang-Berthelsen CH, Fløyel T, Stahl JL, Christen L, Sotudeh FT, et al. MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage. PLoS One 2018;13(9)e0203713. [41] Khan S, Jena GB. Protective role of sodium butyrate, a HDAC inhibitor on betacell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat. Chem Biol Interact 2014;213:1–12. [42] Chou DHC, Holson EB, Wagner FF, Tang AJ, Maglathlin RL, Lewis TA, et al. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol 2012;19(6):669–73.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
Current Research in Translational Medicine xxx (2019) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
General review
Role of HDAC inhibitors in diabetes mellitus Rashita Makkara , Tapan Behla,* , Sandeep Arorab a b
Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India Department of Pharmacy, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 April 2019 Accepted 21 August 2019 Available online xxx
Objective: The role of histone deacetylases has come out as an emerging remedy in control and treatment of various metabolic disorders and cancers. This review highlights their intricate role in diabetes mellitus as well as its associated complications. Key findings: Through recent studies and reports the role of various epigenetic markers in treatment of diabetes mellitus has been revealed. HDAC enzyme regulates the structure of chromatin and transcripts genes in the nucleus synthesizing various proteins that control metabolic activities in the body. It mainly acts by removing an acetyl group from its precursor protein thereby modulating gene expression and regulates the metabolic enzyme acetylation in mitochondria and cytosol. Summary: The present review focus on the intrinsic role of HDAC inhibitors as an emerging remedy for diabetes and its complications demonstrating their use in preventing resistance of β-cells towards insulin, destruction of β-cells and provide protection against cytokine mediated attack on pancreatic cells. © 2019 Elsevier Masson SAS. All rights reserved.
Keywords: Histone deacetylases Insulin resistance Acetylation Transcription β-cell destruction Gene expression
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . Diabetes mellitus . . . . . . . . . . . . . . . . . . Role of HDACs in etiology of diabetes . . HDAC inhibitors and insulin signaling . HDAC inhibitors and activity of β-CELLS HDACs as treatment approach . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . Declaration of Competing Interest . . . . References . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
Introduction Diabetes mellitus allocates a group of chronic diseases where aberrancies in substrate metabolism occur in response to relative or absolute lack of insulin with pronounced long term complications. The disease may be due to inherited or acquired deficiency of insulin synthesis or its inability to bind to receptor and produce effective results. Various body systems particularly the nerves and blood are highly damaged due to increased levels of glucose
* Corresponding author. E-mail addresses: [email protected], [email protected] (T. Behl) .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
00 00 00 00 00 00 00 00 00
making it an essential hallmark of the disease [1]. The WHO last reported the prevalence of diabetes in October 2018 [2]. The number of people affected with the disease has reached to 422 million from 108 million in 1980 and the numbers are supposed to double every ten years. The prevalence of disease has also reached upto 8.5% from 4.7% among the individuals above 18 years in 1980. The low and middle income countries are more exposed to diabetes and it has become one of the major causes of blindness, stroke, lower limb amputations, kidney failure and heart attacks. Diabetes has also been stamped to be the 7th leading cause of death in 2016 by WHO [3,4]. The long recognized causes of type I diabetes include destruction of β-cell and autoimmune islet inflammation though it is still debated whether molecular mechanisms involve predominantly inflammatory cytokine
http://dx.doi.org/10.1016/j.retram.2019.08.001 2452-3186/© 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
2
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
mediated β-cell destruction or classical cytotoxic T-cell mediated killing or both. A number of mechanisms explaining destruction of β-cells have been proposed like glucolipotoxicity, islet amyloid polypeptide deposition mediated disruption of membrane and inflammation of islets. Later, a unified hypothesis was proposed that explained the cause of β-cell destruction by induction of inflammatory mediators in pancreatic islets that further activate pathways in β-cells resembling those in type 1 diabetes (T1D) [5,6]. The inventory processes for developing novel treatment approaches has undergone a revolutionary turn which has aided study and targeting of newer protein molecules with exceptional outcomes. A drug developer is no less than an artist as targeting specific proteins with respect to disease pathology to achieve higher degree of effective treatment with minimal possible side effects is not a job of left hand. The recent trend of drug development has turned to epigenetic modifications in gene expressions of the diseased patient which aims at targeting proteins involved in pathogenesis of the disease. The manner in which DNA is packaged profoundly influences the transcription of genes in eukaryotic cells. The stable and potentially reversible alteration in gene expressions of an individual without any permanent change in DNA sequence with inheritance property is called epigenetic modifications [7]. Waddington originally defined epigenetics as a firm reason for programmed changes during development of embryo due to interactions between genes and their products bringing out a phenotypic change. The bridge between environment and genetics is epigenome while determining the final phenotype on modification of gene expressions without any alteration in DNA sequence is epigenetic code. By targeting the specific gene directly, the phenotype of the disease can be changed through epigenetic modifications in response to pathological and environmental conditions like diet, exercise, toxins, inflammation, oxidative stress and metabolic changes. The epigenetic modifications show a phenomenal role in genomic imprinting, stable inheritance of gene expression, embryonic development, cell differentiation and identity, inactivation of X chromosome, immune cell functioning, and responses to environmental signals at cellular levels [8]. One such emerging epigenetic modification that is being investigated recently is Histone modification. It has managed to obtain exceptional results in treatment of severe life threatening diseases including cancer and metabolic disorders [9]. Gene transcription processes in cells of eukaryotes depend highly upon the chromatin confirmation. Nucleosome is the basic unit of chromatin constituting four core dimers of histones namely H2A, H2B, H3 and H4 which are doubly folded around the DNA in the form of an octamer. The covalent modifications undergo in the basic N-terminal tail of histone proteins which recruit factors responsible for transcription via changes in structure causing packaging of chromatin and regulate gene expression [10]. The remodeling of chromatin through acetylation, phosphorylation, methylation and various other posttranslational modifications in histones is the fundamental phenomenon in eukaryotic cell biology highlighting diverse approaches for treatment in response to physiological and pathological conditions. The histone acetyl transferase (HAT) and histone deacetylase (HDAC) as their name suggests acetylate and deacetylate histone proteins respectively [11,12]. The HAT enzyme undergoes posttranslational histone acetylation by transferring an acetyl group from acetyl coenzyme A to the e-NH3 groups of internal residues of histone proteins. Acetylation forms decondensed chromatin called ‘euchromatin’ by neutralizing the positive charge on tail of N-terminal residues of lysine. This decreases the propensity of positive terminal residues towards DNA activation, increasing access of DNA towards transcription factors and RNA polymerase by unfolding nucleosomes and causes gene activation. In contrast to HAT, the enzyme HDAC acts by
removing acetyl group from histone lysine residues and restores the persisting positive charge on terminal tails of Nitrogen therefore increasing their likeliness for DNA. The tails displace transcription factors and forms a repressive structure of chromatin hence suppress transcription [13]. The mammalian HDACs can be divided into two families and four classes. The first family includes category of HDACs that are classically Zinc ion dependent while the other family is nicotinamide adenine dinucleotide (NAD) dependent HDACs. The Zn dependent family of HDACs includes: Class I HDACs: It comprises of HDAC isoforms 1, 2, 3 and 8. These HDACs are localized and found exclusively in the nucleus and are related to Rpd3 yeast enzyme with homology shared in catalytic pocket. Class II HDACs: It is advanced into two categories which is Class IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10). It covers two homology regions, in Nitrogen terminal regulatory area and Carbon terminal area of catalysis. The HDACs circulate between nucleus and cytosol with certain recruitment of protein complexes and deacetylation sites occur. Class IV HDACs: They comprise only one member i.e. HDAC 11. It is found in both nucleus as well as cytoplasm. The NAD+ dependent family of HDACs include: Class III HDACs: They are also called the silent information regulator 2. The HDAC enzymes are dependent on NAD+ under presence of which acetyl groups are removed from residues of acetylated lysine. This class includes homology of yeast Sir 2, which in presence of cofactor NAD acts as a vital protein for silencing certain genes and catalyze their action. They are also called Sirtuins. Till now seven members have been noted in the family of protein sirtuin localized in mitochondria, nucleus and cytoplasm of the cell [14]. The deacetylation action of HDAC 6 is higher on 5th and 8th lysine residue of histone 4 while HDAC 1 and 3 have been tested for their efficacy to deacetylate the lysine residues containing four core histones on varied levels [15,16] (Table 1). HDAC inhibitors through hyperacetylation of non histone and nucleosomal histone proteins regulate expression of genes. Most of the HDACs are large multiprotein complex regulated and do not activate enzymatically without interacting with other proteins. NuRD/Mi2, coREST, Sin3, and N-CoR and SMRT, the nuclear receptor corepressors are some of the multiprotein complexes required in the activation of HDAC proteins. The SMRT and N-coR nuclear receptor complexes enzymatically activate HDAC3 whereas the other complexes i.e. the Sin 3, CoREST and NuRD/Mi2 complexes stimulate the activity of HDAC1and HDAC2 deacetylase. Class IIa HDACs recruit HDAC3 comprising N-CoR/SMRT active complexes and are inactive HDACs. HDACs and its inhibitors predominantly control cell proliferation, differentiation, apoptosis and also modulate cell cycle by regulating cellular reactions [17,18]. HDACs have multiple actions as they target numerous cellular pathways and produce resultant responses. HDACs bind to nuclear receptors and regulate signaling of hormones by modulating their release. This indicates its use in management of diabetes mellitus as HADCs stimulate release of insulin. The α-tubulin proteins are expressed in the cytosol of the cells. HDAC 6 is highly specific and binds to α-tubulin and actin proteins which control the stability and functioning of microtubules. The acetylation state of actin is highly modulated by HDAC6 thereby blocking its fibrillar action and affects actin dependent motility. Angiogenesis is also prevented by use of HDAC inhibitors as angiogenic markers like VEGF and HIF-1α are targeted by HDACs The role of HDACs in modulating inflammation by suppressing outburst of inflammatory mediators has already been discussed in the article.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
3
Table 1 An overview of HDACs. CLASS
NAME
LOCATION
Co - FACTOR
EXPRESSING TISSUES
USES
CLASS I
HDAC 1 HDAC 2 HDAC 3 HDAC 8 HDAC 4 HDAC 5 HDAC 7 HDAC 9 HDAC 6 HDAC 10 SIRT 1 SIRT 2 SIRT 3 SIRT 4 SIRT 5 SIRT 6 SIRT 7 HDAC 11
Nucleus
Zn2+ DEPENDENT
Widespread
Inflammation, Insulin resistance
Heart, Brain Smooth muscle Placenta, Pancreas, Heart Smooth muscle, Brain Kidney, Liver, Heart Spleen, Kidney, Liver White adipose tissue Testes, Heart, Brain Brown adipose tissue Islets of pancreas Liver
Hyperglycemia, Insulin resistance, Decreased insulin production
CLASS II (a)
CLASS II (b) CLASS III
CLASS IV
Nucleus/Cytoplasm Nucleus Nucleus/Cytoplasm
Nucleus, Cytoplasm Cytoplasm Mitochondria
+
NAD DEPENDENT
Nucleus Nucleus
Zn2+ DEPENDENT
HDACs suppress tumor growth by binding to p53, p21 and cyclin proteins and alter cell cycle of the body. Diabetes mellitus The main source of energy for most of the cellular functions is glucose. An increased level of circulating glucose in body post meal stimulates pancreatic β cells to release insulin. Insulin plays an important role in glucose homeostasis. It undergoes autophosphorylation on binding with transmembrane receptors and phosphorylates the intercellular protein substrates including insulin receptor substrate – 1 and 2 (IRS-1 and IRS- 2). The phosphorylated IRS subsequently activates phosphoinositide 3kinase (PI3K/AKT) pathway. These phosphorylated products stimulate activation of several enzymes and proteins and translocate glucose transporter 4 (GLUT 4) to cell membrane from intracellular cell vesicles. An array of metabolic events is demonstrated by another important pathway in insulin signaling called mitogen activated protein kinase (MAPK) pathway [19]. Over the last century drastic behavioural and lifestyle changes have produced conditions of insulin resistance where amidst the presence of abundant amount of insulin, it is no longer able to bind to its receptor causing prohibition of any further series of events [20]. Diabetes can be categorized into two principal forms: Type I diabetes: formerly known as insulin dependent diabetes, is a condition where pancreas fails to synthesize insulin hence disturbing homeostasis of glucose in body. It is frequently observed in children and adolescents and is termed juvenile diabetes. Type II diabetes: also known as non-insulin dependent diabetes, is a condition in which the body fails to respond to pre-existing insulin. About 90% of diabetic cases worldwide are accounted to be T2D and predominantly targets adults [21]. Mutations in one or more genes by genetic-environmental interactions trigger onset of diabetes making it a complex disease. Both the types of diabetes are genetically distinct where type I diabetes is believed to happen due to variations in immune regulatory genes highlighting its autoimmune nature and exposing individuals to T-cells driven β-cell destruction and chronic inflammation whereas in contrast genome wide association scans (GWAS) suggested type II diabetes as a disease where alterations in genes evoke changes on β-cell function and impairs its compensation to increased demands of insulin [1]. The immune and metabolic pathogenesis of both types of diabetes seems to
Heart, Smooth muscle, Brain, Kidney
Glucose intolerance, Hyperglycemia Enhanced insulin signaling Impaired insulin signaling Enhanced insulin signaling Impaired insulin signaling Enhanced insulin signaling Impaired insulin signaling Enhanced insulin signaling Inflammation
converge on common extracellular inflammatory stressors despite their dissimilar genetic background and these stressors induce intracellular signaling in islet cells. The most commonly reported intracellular stressors is IL-1β which is secreted from activated mononuclear cells that prohibit functioning of β-cell and cause cell death on prolonged exposure due to their selective β-cell toxicity [22,23]. The molecular performance of HDAC was assumed to be limited to deacetylation as indicated by their name but recent advances in phylogenetic analysis suggested their role in regulating performance in a broader range of non histone proteins. In terms of posttranslational mechanisms the impact of acetylation is no less than phosphorylation increasing demand of HDACi as a treatment approach for an expanding range of diseases. The original goal of HDAC inhibition was transcriptional control over oncogene networks in cancer cells but their indications as novel treatment in other diseases including neurodegenerative and inflammatory diseases is growing exceptionally. The master transcription factor nuclear factor (NF-kB) in inflammation is now recognized to be regulated by acetylation. In the current review the prospects of inhibition of HDAC as a novel approach for treatment of diabetes will be reviewed. It also incorporates an outline of genetic associations relating to etiology of diabetes and HDACs and evaluating its potential as an oral therapy in treatment of disease and its associated complications depending upon the pathological events [24,25]. Role of HDACs in etiology of diabetes A combination of environmental and genetics factors contribute in the etiology of diabetes making it complex. Though T1D and T2D are considered to be genetically distinct, an association between the 6q21 chromosomal region has been identified by genome wide association scans (GWAS) studies where HDAC 2 is also located signifying the latter’s role in both the diabetes. The epigenetic and environmental factors significantly contribute in the etiology of the disease making it a polygenetic disorder. Simmons and Pinney reported that an unfavorable fetal milieu due to exposure of fetus to intra uterine growth retardation (IUGR) affects the development of β-cells due to modification in muscular transport of glucose by glucose transporter 4 (GLUT 4) and varying key regulatory genes like pancreatic and duodenal homeobox factor 1 (Pdx1) thereby advancing to T2D. Loss of acetylation of histone recruits HDAC1 which complexes Pdx1 a proximal
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
4
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
promoter to the Sin3A corepressor hence reducing the expression of Pdx1after IUGR. The HDAC1/Sin3 complex formed propagates epigenetic cycle and recruits histone demethylase which inhibits the transcription of Pdx1 thereby causing loss of histone 3 lysine 4 trimethylation (H3K4me3). Inhibition of HDACs reverses this effect by methylation and dimethylation of H3K9 which lodges the promoter Pdx1 in its transcriptionally inactive state [26]. The transcription of Glut4 is inhibited as a result of lack of histone acetylation in adult muscle tissue of Glut 4 promoter as mediated by HDAC1 and HDAC4 thereby repressing the peripheral uptake of glucose and producing insulin resistance thus contributing to T2D. The remodeling of chromatin in incretin hormones such as glucose dependent insulinotropic peptide 1 and glucagon-like peptide 1 has already been induced as a therapeutic approach in treatment of T2D which has led to greater association with the transcription factors due to in vitro global acetylation of H3 histones [27,28]. HDACs and histone acetylation are also useful in treatment of rare kinds of autosomal diabetes namely “maturity onset diabetes of the young” (MODY) and its seven dissimilar subtypes based on the mutations in genes apart from their clinical relevance in treatment of T1D and T2D. The genes encode nearly all transcription factors which are involved in the production of insulin and development of pancreas except for insulin and glucokinase. Some of these include hepatocyte nuclear factor (HNF)- 1α, -1β and -4α which produces hepatic gluconeogenesis and transcription of insulin, neurogenic differentiation 1 (NeuroD1) and Pdx1. Histone acetyl transferases (HATs) and HDACs by remodeling chromatin interact with the transcription factors and regulate normal functioning suggesting their important role in pathogenesis of diabetes [29]. HDAC inhibitors and insulin signaling The signaling of insulin is vital in maintaining the glucose homeostasis in body as a decline in its signaling inhibits hepatic steatosis in liver and containment of gluconeogenesis with reduced uptake of glucose in muscles. Insulin signaling also regulates the mass of β-cells which is directly involved in onset and progression of diabetes [30]. The Fig. 1 below describes the pathway for insulin signaling. On binding to insulin receptor, the autophosphorylation and phosphorylation of insulin receptor substrate (IRS) family members occurs causing release and action of insulin. The IRS proteins post phosphorylation bind and activate phosphatidylinositol 3-kinase which further stimulate protein kinase Akt phosphorylation ultimately translocating glucose transporter (GLUT 4) to the plasma membrane from intracellular vesicles and mediating uptake of glucose. The myocyte enhancer factor (MEF)-2 and GLUT 4 enhancer factor (GEF) are chief
regulators that control translocation of GLUT 4 by binding to its translational elements [31]. The obstruction in release of insulin may occur at several stages. There are two mechanisms that control the signaling of insulin in β-cells through HDACs, firstly through epigenetic control while secondly through IRS2 expression and activity regulation via protein acetylation [32]. The role of IRS2 has been reported to be very crucial in proliferation of β-cells of pancreas hence identifying and employing a precise isoform of HDAC can be a valuable approach as therapy forT2D [33]. The HDAC1 located in nucleus acts via acetylation of histone in the promoter region of IRS2 while the cytoplasm localized HDAC acetylates the lysine residues in IRS2 and leads to modification of proteins [34]. The expression of different isoforms of HDACs differed in the brain with altered activity in kidneys of diabetic patients. The differentiation of β-cells of pancreas was reported to be controlled by HDAC 4, 5 and 9. An increased expression of HDAC1 was encountered from pancreatic cells isolated from children with T1D with decrease in HDAC2 and HDAC3 expressions. The secretion of insulin is suppressed by histone acetylation and promoted expression of Tcf7l2 with increased articulation of HDAC7 in pancreatic cells of T2D patients. The acetylation of lysine in SREBP 1a and p53 inhibits ubiquitination while acetylation of lysine in PGC1α and FOXO promotes autophosphorylation. The phosphorylation of tyrosine in neuronal cells seems to diminish on IRS2 post translational modification due to acetylation of lysine in IRS2 with no reports β cells of pancreas [35,36]. The patients receiving HDAC inhibitors as therapy for treatment of cancer have been reported to fabricate hyperglycemia as its consequence indicating its role in signaling of insulin in some organs with impairment of tolerance to glucose. Hence through these findings the need to pick more selective HDAC inhibitors can be suggested necessary to provide protective effect for insulin signaling [37,1] (Fig. 2). HDAC inhibitors and activity of β-CELLS The factors mediating transcription play crucial role in development of pancreas by differentiation of endocrine and exocrine. The etiology of type-1 diabetes is highlighted by the understanding of mechanism of apoptosis of β-cells induced by inflammatory cytokines. The molecules with capability to suppress this apoptotic processes can be efficiently employed as therapy for preventing β-cells from hypersensitive reactions and immune responses. Various studies have reported the protective actions of HDAC inhibitors in preventing destruction of β-cells [38]. The determination of precise isoform of HDAC which is responsible for survival of β-cells is fundamental to its therapeutic application as
Fig. 1. signaling pathways associated with HDACs.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
5
proteins accumulate on HDACi treatment modifying their functions [41,42]. The targets in pancreas that can are involved in etiology of DM are also under investigation for contributing better in expression and regulation of Ngn3. Hence through various studies the role of HDACs in proliferation of β-cells has been stated evident as they have direct effects on fate regulation of endocrine cells [1] (Fig. 3). HDACs as treatment approach
Fig. 2. Mechanism of Insulin Signaling.
broad spectrum HDAC inhibitors may have toxic effects and fail to restore significant β-cell functions like secretion of insulin as stimulated by levels of glucose [39]. Genetic and chemical inhibition of HDAC3 has been found to suppress the apoptosis of β-cell line of rats. The selective HDAC 1, 2 and 3 inhibitors embarked better protective effects in β-cell line as compared to broad spectrum HDAC inhibitors like SAHA indicating additional side toxicities induced by inhibition of various isoforms of HDAC. MS-275 a selective HDAC inhibitor he genetic knock down of HDAC3 stimulated secretion of insulin in response to glucose levels and restores it [40]. The development of endocrine progenitors of NGN3+ was enhanced on treatment with HDACi. The epithelial cells in pancreas contain precursors for PDX1+ which augments development of various cell types of pancreas besides NGN3+ cells. On enhancing proliferation of precursors of PDX1+ by FGF 10 or mesenchyme the progenitors of endocrine NGN3+ are intensified. On initiating treatment with HDACi no increase in the production of PDX1+ precursors was noticed indicating role of HDACi and FGF 10 in enhancing the endocrine progenitors NGN3+ in alternate ways except for poorly growing cells of NGN3+ making it independent of proliferation of cells. Also the relationship between the β-cell signaling of transforming growth factor in differentiation of pancreatic cells is being investigated. A possibility of HDACi to inhibit the promoter NGN3+ cells directly as mechanism of action is being explored for its therapeutic efficiency. The presence of non histone substrates of proteins in HDACi regulates expression of genes and also controls death and proliferation of cells. The acetylated forms of these substrate
Various HDACi have recently been approved by FDA e.g., Panobinostat is under phase IV clinical trials and has also been approved by FDA in 2015 for its use in management of multiple myeloma and cutaneous T-cell lymphoma (CTCL) Some of the HDACi under clinical trials include: Valproic acid is under phase III clinical trials for its use in cervical and ovarian cancer. Tacedinaline, another HDACi is under phase III trials for its use in management of multiple myeloma and lung cancer. Mocetinostat is under phase II clinical trials for its use in management of Follicular and Hodgkin lymphoma and acute myeloid leukemia. Rocilinostat has been recently developed and is under phase I trials for its use in treatment of multiple myelomas. Many other HDAC inhibitors drugs like Mocetinostat, Abexinostat, Practinostat are under phase II clinical trials and are being studied for their beneficial effects in treatment of Follicular and Hodgkin lymphoma and acute myeloid leukemia, Sarcoma and lymphoma and Recurrent or metastatic prostate cancer respectively. Some of the HDACs used in management of diabetes mellitus include: Vorinostat (SAHA) was the first HDAC inhibitor to be approved by FDA in 2006 for its use in treatment of cutaneous T-cell lymphoma. Apart from its use in myeloma, SAHA is also being examined for its therapeutic role in management of diabetes mellitus as its is reported to increase expression of insulin even in low concentrations of glucose. Sodium butyrate (NaB) and Trichostatin A (TSA) are other HDACi that are simultaneously being examined for their use in diabetes mellitus. TSA is believed to increase insulin release by stimulating expression of β-cells and stimulating GLP-1 proteins. TSA also improved the transdifferentiation of bone marrow stem cells into insulin-producing cells Sodium butyrate (NaB) stimulates early events of pancreatic specification in embryonic stem (ES) cells by promoting their differentiation into insulin-producing cells. Valproate has been used commonly in treatment of bipolar disorders and other CNS disorders. A typical side effect associated with Valproate was hyperinsulinemia. It was found that the function is attributed to inhibition of HDACs by Valproate. Hence,
Fig. 3. HDAC inhibitors and β-cell destruction.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001
G Model RETRAM 3233 No. of Pages 6
6
R. Makkar et al. / Current Research in Translational Medicine xxx (2019) xxx–xxx
valproate is also under study for evaluation of its effect in management of diabetes mellitus. Various other HDACi like Romidepsin, Panabiostat have been approved by FDA for management of lymphomas and their role in diabetes is yet under investigation. Conclusion HDACs are indulged in multiple biological system pathways and contribute majorly in pathogenesis and development of diabetes mellitus even through genetic basis. HDACs promote development, proliferation and differentiation of β-cells and regulate their functioning by preventing inflammatory cell damage, improve resistance of insulin and prevent microvascular complication of diabetes at later stages. Altogether it can be summoned that HDACi can be initiated as promising therapy for preventing and treating diabetes and its clinical utility is under examination as there is still a lot to be learned about its mechanism. Declaration of Competing Interest The author(s) declare no conflict of interest. References [1] Christensen DP, Dahllöf M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N, et al. T. HDAC inhibition as a novel treatment for diabetes mellitus. 2011. [2] Kaiser AB, Zhang N, Van der Pluijm W. Global prevalence of type 2 diabetes over the next ten years (2018–2028). 2019. [3] Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus: present and future perspectives. Nat Rev Endocrinol 2014. [4] Frier BM. Hypoglycaemia in diabetes mellitusA and clinical implications. Nat Rev Endocrinol 2014;10(12):711. [5] Adeghate E, Schattner P, Dunn E. An update on the etiology and epidemiology of diabetes mellitus. Ann N Y Acad Sci 2006;1084(1):1–29. [6] Alonso-Magdalena P, Quesada I, Nadal A. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol 2011;7(6):346. [7] Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010;28(10):1057. [8] Kanwal R, Gupta S. Epigenetic modifications in cancer. Clin Genet 2012;81 (4):303–11. [9] Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol 2010;28(10):1069. [10] Abel T, Zukin RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 2008;8(1):57–64. [11] Shen Y, Wei W, Zhou DX. Histone acetylation enzymes coordinate metabolism and gene expression. Trends Plant Sci 2015;20(10):614–21. [12] Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet 2016;17:487–500. [13] Schütz LF, Park MH, Choudhury M. HDACs in diabetes: a new era of epigenetic drug. Nutritional and therapeutic interventions for diabetes and metabolic syndrome. second edition . p. 475–86. [14] Yang XJ, Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 2007;26:5310–8. [15] Sengupta N, Seto E. Regulation of histone deacetylase activities. J Cell Biochem 2004;93:57–67. [16] Kelly RD, Cowley SM. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem Soc Trans 2013;41:741–9. [17] Mathias RA, Guise AJ, Cristea IM. Post-translational modifications regulate class IIa histone deacetylase (HDAC) function in health and disease. Mol Cell Proteomics 2015;14:456–70.
[18] Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997;389:349–52. [19] Sharma S, Taliyan R. Histone deacetylase inhibitors: future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res 2016;113:320–6. [20] Ye J. Improving insulin sensitivity with HDAC inhibitor. Diabetes 2013;62:685–7. [21] Baynes HW. Classification, pathophysiology, diagnosis and management of diabetes mellitus. J Diabetes Metab 2015;6(5):1–9. [22] DMICC. Genetic basis of type 1 and type2 diabetes, obesity, and their complications. Advances and emerging opportunities in diabetes research: a Strategic Planning report of the DMICC. 2014. [23] Pablo A. Recent advances in understanding/managing type 2 diabetes mellitus. F1000Research 2017;6. [24] Sharma S, Taliyan R. Histone deacetylase inhibitors: future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res 2016;113:320–6. [25] Gray SG, De Meyts P. Role of histone and transcription factor acetylation in diabetes pathogenesis. Diabetes Metab Res Rev 2005;21:416–33. [26] Pirola L, Balcerczyk A, Okabe J, El-Osta A. Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol 2010;6(12):665. [27] Sathishkumar C, Prabu P, Balakumar M, Lenin R, Prabhu D, Anjana RM, et al. Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics 2016;8(1):125. [28] Patel MM, Patel BM. Repurposing of sodium valproate in colon cancer associated with diabetes mellitus: role of HDAC inhibition. Eur J Pharm Sci 2018;121:188–99. [29] Hull EE, Montgomery MR, Leyva KJ. HDAC inhibitors as epigenetic regulators of the immune system: impacts on cancer therapy and inflammatory diseases. Biomed Res Int 2016. [30] Rafehi H, Kaspi A, Ziemann M, Okabe J, Karagiannis TC, El-Osta A. Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes. Epigenetics 2017;12(11):991–1003. [31] Anuradha R, Saraswati M, Kumar KG, Rani SH. Apoptosis of beta cells in diabetes mellitus. DNA Cell Biol 2014;33(11):743–8. [32] Remsberg JR, Ediger BN, Ho WY, Damle M, Li Z, Teng C, et al. Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion. Mol Metab 2017;6(1):30–7. [33] Khan S, Jena G. Valproic acid improves glucose homeostasis by increasing beta-cell proliferation, function, and reducing its apoptosis through HDAC inhibition in juvenile diabetic rat. J Biochem Mol Toxicol 2016;30(9):438–46. [34] McGee-Lawrence ME, Pierce JL, Yu K, Culpepper NR, Bradley EW, Westendorf JJ. Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity. J Cell Physiol 2018;233(4):2671–80. [35] Lundh M, Galbo T, Poulsen SS, Mandrup-Poulsen T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes Metab 2015;17(7):703–7. [36] Kawada Y, Asahara SI, Sugiura Y, Sato A, Furubayashi A, Kawamura M, et al. Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells. PLoS One 2017;12(9)e0184435. [37] Sun C, Zhou J. Trichostatin A improves insulin stimulated glucose utilization and insulin signaling transduction through the repression of HDAC2. Biochem Pharmacol 2008;76(1):120–7. [38] Sabir S, Saleem A, Akhtar MF, Saleem M, Raza M. Increasing beta cell mass to treat diabetes mellitus. Adv Clin Exp Med 2018. [39] Larsen L, Tonnesen M, Ronn SG, Størling J, Jørgensen S, Mascagni P, et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia 2007;50(4):779–89. [40] Vestergaard AL, Bang-Berthelsen CH, Fløyel T, Stahl JL, Christen L, Sotudeh FT, et al. MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage. PLoS One 2018;13(9)e0203713. [41] Khan S, Jena GB. Protective role of sodium butyrate, a HDAC inhibitor on betacell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat. Chem Biol Interact 2014;213:1–12. [42] Chou DHC, Holson EB, Wagner FF, Tang AJ, Maglathlin RL, Lewis TA, et al. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol 2012;19(6):669–73.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/ 10.1016/j.retram.2019.08.001