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Acta Pharmaceutica Sinica B 2012;2(4):387–395 Institute of Materia Medica, Chinese Academy of Medical Sciences Chinese Pharmaceutical Association

Acta Pharmaceutica Sinica B www.elsevier.com/locate/apsb www.sciencedirect.com

REVIEW

Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications in diabetes mellitus Xiaojie Wanga, Xinbing Weia, Qi Pangb, Fan Yia,n a

Department of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

b

Received 10 April 2012; revised 16 May 2012; accepted 7 June 2012

KEY WORDS Histone deacetylases; Diabetes mellitus; Histone acetyltransferases; HDAC proteins; HDAC inhibitors

Abstract Epigenetic mechanisms such as DNA methylation, histone modification and microRNA changes have been shown to be important for the regulation of cellular functions. Among them, histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone acetyltransferases in chromatin remodeling and play essential roles in gene transcription to regulate cell proliferation, migration and death. Recent studies indicate that HDACs are promising drug targets for a wide range of diseases including cancer, neurodegenerative and psychiatric disorders, cardiovascular dysfunction, autoimmunity and diabetes mellitus. This review highlights the role of HDACs in diabetes mellitus and outlines several important cellular and molecular mechanisms by which HDACs regulate glucose homeostasis and can be targeted for the treatment of diabetic microvascular complications. It is hoped that our understanding of the role of HDACs in diabetes mellitus will lead to the development of better diagnostic tools and the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease. & 2012 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved.

n

Corresponding author. Tel./fax: þ86 0531 88382616. E-mail address: [email protected] (Fan Yi).

2211-3835 & 2012 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved. Peer review under the responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. http://dx.doi.org/10.1016/j.apsb.2012.06.005

388 1.

Xiaojie Wang et al. Introduction

Histone deacetylases (HDACs) are enzymes that balance the activities of histone acetyltransferases (HATs) in chromatin remodeling and thereby play an essential role in gene transcription to regulate cell proliferation, migration and apoptosis, immune pathways and angiogenesis. In the last few years, numerous studies have demonstrated the role of HDACs in cancer initiation and progression giving rise to the view that HDACs are potentially important drug targets in the treatment of cancer. Recent studies also indicate that targeting HDACs is a promising therapeutic strategy for a number of other diseases including neurodegenerative disorders, cardiovascular dysfunction, autoimmunity and diabetes mellitus. This review highlights the role of HDACs in the regulation of glucose metabolism, insulin resistance, insulin expression and secretion and the therapeutic potential of HDAC inhibitors for the treatment of diabetes mellitus. It is hoped that clarification of the pathological role of HDAC-mediated signaling pathways will aid in the development of diagnostic tools and in the design of more potent and specific drugs that target individual HDAC proteins.

2.

The HDAC family: classification, location and substrates

HDACs are a family of enzymes which compete with HATs to control the acetylation of lysine residues making up the histones. The balance of acetylation and deacetylation then determines the post-translational acetylation status of histone and other non-histone proteins1. To date, 18 HDACs have been identified in mammals made up of four classes according to their sequence identity and catalytic activity2. Class I HDACs (HDAC1, 2, 3 and 8) share sequence homology with the yeast Rpd3 protein and contain a nuclear localization signal (NLS) but, with the exception of HDAC3, no nuclear export signal (NES). Accordingly, they are mainly located in the nucleus and regulate the expression of many genes3, such as thioredoxin binding protein-2 (TBP-2), myocyte enhancer factor-2 (MEF2), NF-kB and GATA4. Class II HDACs (HDAC4–7, 9 and 10) are larger proteins than class I because they contain additional regulatory domains. They contain both an NLS and NES and shuttle between the cytoplasm and nucleus depending on their phosphorylation status. Class II HDACs are further subdivided into class IIa (HDAC4, 5, 7, 9) and IIb (HDAC6, 10) with class IIa having relatively low enzymatic activity compared to class I possibly to allow them to efficiently process restricted sets of specific, unknown natural substrates. Class IIb HDACs have primarily non-epigenetic functions involving the regulation of protein folding and turnover5,6. HDAC11 is the sole member of class IV. It is localized in the nucleus and has a catalytic domain in the N-terminal region. HDAC11 has been demonstrated to regulate the balance between immune activation and immune tolerance in CD4þ T-cells7 and to play an essential role in oligodendrocyte differentiation8 and the regulation of OX40 ligand expression in Hodgkin lymphoma9. Classes I, II and IV HDACs possess a Zn2þ-dependent mechanism of action whereas the structurally unrelated class III HDACs comprise a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases sharing sequence

homology with the yeast Sir2 protein10,11. Because of this, class III HDACs are also called ‘sirtuins’ (SIRTs). SIRTs 1–7 target a wide range of cellular proteins in the nucleus, cytoplasm and mitochondria for post-translational modification by acetylation or ADP-ribosylation. Among them, SIRT1 and SIRT2 can shuttle between the nucleus and cytoplasm12,13. SIRT1, the founding member of the class, couples protein deacetylation with NADþ hydrolysis and links cellular energy and redox state to multiple signaling and survival pathways which positively regulate transcription factors such as NF-kB, p53 and forkhead box (FOX) proteins. In addition, SIRT1 may play a role in tumor initiation and progression as well as in the development of drug resistance by blocking senescence and apoptosis or promoting cell growth and angiogenesis. SIRT2 is mainly localized to the cytoplasm and affects a-tubulin acetylation status. SIRTs 3, 4 and 5 are mainly localized in the mitochondria14. SIRT3 helps to maintain energetic cell homeostasis by positively regulating the activity of acetylcoenzyme A synthetase 2 and deacetylating complex I of the respiratory chain involved in ATP production. SIRT4 has ADP ribosylase activity which inactivates glutamate dehydrogenase and, in turn, inhibits insulin secretion in pancreatic b-cells. SIRT5 deacetylates and thereby activates carbamoyl phosphate synthetase 1 to promote ammonia detoxification. SIRTs 6 and 7 are predominantly found in the nucleus where they are involved in DNA repair and ribosomal RNA transcription, respectively. To date, sirtuins have emerged as potential therapeutic targets for the treatment of cancer and of metabolic, cardiovascular and neurodegenerative diseases. This review focuses on the Zn2þ-dependent HDACs because they are the targets of small molecule HDAC inhibitors that have shown efficacy in animal models of diabetes mellitus. The classification, location, substrates, main biological functions and inhibitors of HDACs are shown in Table 1.

3.

HDAC inhibitors

HDAC inhibitors are chemical compounds that inhibit Zn2þdependent HDAC enzymes and for which some 490 clinical trials have been carried out over the last 10 years. Their efficacy against malignant cells and their potent anticancer activity in pre-clinical studies have been demonstrated. They also display protective effects in animal models of various neurological and cardiovascular diseases and of diabetes mellitus15–17. HDAC inhibitors can be structurally grouped into hydroxamates, cyclic peptides, aliphatic acids, benzamides, boronic acid-based compounds, benzofuranone and sulfonamide containing molecules and a/b peptide structures18. Most of them possess a stereotypical three-part structure consisting of a zinc-binding ‘‘warhead’’ group which docks in the active site, a linker, and a surface recognition domain which interacts with residues near the entrance of the active site. Among them, vorinostat (suberoylanilide hydroxamic acid) and depsipeptide (Romidepsin, FK-228) were approved by the FDA in 2006 and 2009, respectively. Vorinostat is structurally related to trichostatin A (TSA) which is indicated for the treatment of relapsed and refractory cutaneous T-cell lymphoma (CTCL). The cyclic peptides are the most structurally complex group of HDAC inhibitors of which depsipeptide is one of the most important members.

Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications in diabetes mellitus

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The HDAC family: classification, localization and substrates.

Table 1 HDAC

Location

Substrates

Biological functions

Main HDAC inhibitor

Cell survival and proliferation

Valproic acid, vorinostat, TSA, RGFP1-36 (HDAC3)

Class Member I

HDAC1

HDAC2 HDAC3

IIa

HDAC8 HDAC4

HDAC5

IIb

III

IV

Nucleus

Histones, MEF2, GATA, YY1, NF-kB, DNMT1–SHP, ATM, MyoD, p53, AR, BRCA1, MECP2, pRb Nucleus Histones, HOP, NF-kB, GATA2, BRCA1, pRb, MECP IRS-1 Nucleus Histones, HDAC4, 5, 7–9, SHP, GATA1, NF-kB, pRb Nucleus HSP70 Nucleocytoplasmic Histones, SRF, Runx2, p53, p21, GATA, traffic FOXO, HIF-1a, SUV39H1, HP1, HDAC3, MEF2, CaM, 14-3-3 Nucleocytoplasmic Histones, HDAC3, YY1, MEF2, traffic Runx2, CaM, 14-3-3

HDAC7

Nucleocytoplasmic Histones, HDAC3, MEF2, PML, traffic Runx2, CaM, 14-3-3, HIF-1a

HDAC9

Nucleus

HDAC6

Cytoplasm

Histones, HDAC3, MEF2, CaM, 14-3-3

a-tubulin, Cortactin, HSP90, HDAC11, SHP, PP1, Runx2, LcoR HDAC10 Nucleocytoplasmic LcoR, PP1 traffic SIRT1 Nucleus Histones, p53, p73, p300, NF-kB–FOXO, PTEN, NICD, MEF2, HIFs, SREBP-1c, bcatenin, PGC1a, Bmal, NF-kB, Per2, Ku70, XPA, SMAD7, Cortactin, Ku70, IRS-2, APE1, PCAF, TIP60, p300, AceCS1, PPARg, ER-a, AR, LXR SIRT2 Nucleus Histones, a-tubulin SIRT3

Mitochondria

SIRT4 SIRT5 SIRT6 SIRT7 HDAC11

Mitochondria Mitochondria Nucleus Nucleus Nucleus

Histones, Ku70, IDH2, HMGCS2, GDH, AceCS, SdhA, SOD2, LCAD GDH Cytochrome c, CPS1 Histone H3, TNF-a p53 Histones, HDAC6, Cdt1

Insulin resistance; cell proliferation Cell survival and proliferation Cell proliferation Regulation of skeletogenesis and gluconeogenesis Cardiovascular growth and function; cardiac myocytes and endothelial cell function; gluconeogenesis Thymocyte differentiation– endothelial function– gluconeogenesis Thymocyte differentiation; cardiovascular growth and function Cell motility–control of cytoskeletal dynamics Homologous recombination Aging; redox control–cell survival–autoimmune system regulation

TSA, vorinostat, phenylbutyrate

Vorinostat, TSA, tubacin (HDAC6) Nicotinamide (SIRT1), suramin (SIRT1 and SIRT2)

Cell survival–cell migration and invasion Redox control Enegry metabolism Urea cycle Metabolic regulation Apoptosis Immunomodulators–DNA replication

Sodium butyrate, TSA, vorinostat

AceCS, Acetylcoenzyme A synthetase; AR, Androgen receptor; ATM, Ataxia-telangiectasia-mutated; APE, Apurinic/apyrimidinic endonuclease-1; BRCA, Breast cancer; Bmal, Brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like; CaM, Calmodulin; CPS1, Carbamoyl phosphate synthetase 1; DNMT, DNA methyltransferase; ER-a, estrogen receptor-a; FOXO, Forkhead box O; GATA, GATA binding protein; GDH, Glutamate dehydrogenase; HP1, Heterochromatin protein 1; HMGCS, Hydroxymethylglutaryl-CoA synthase; HOP, Homeodomain only protein; HIF, Hypoxia-inducible factor; HSP, Heat shock protein; IDH, Isocitrate dehydrogenase; IRS, Insulin receptor substrate; LCAD, Long chain acyl coenzyme A dehydrogenase; LcoR, ligand-dependent receptor co-repressor; LXR, Liver X receptor; MECP, Methyl-CpG-binding domain protein; MEF, myocyte enhancer factor; NICD, Notch1 intracellular domain; NF-kB, Nuclear transcription factor-kappa B; PCAF, p300/CBP-associated factor; Per-2, Period circadian protein homolog-2; PTEN, Phosphatase and tensin homolog; PGC, Peroxisome proliferator-activated receptor gamma coactivator; PP1, Protein phosphatase; PPAR, Peroxisome proliferator-activated receptor; pRb, Retinoblastoma protein; PML, Promyelocytic leukaemia protein; Runx, Runt-related transcription factor; SdhA, Succinate dehydrogenase complex subunit A; SHP, Src homology region 2-domaincontaining phosphatase; SOD, Superoxide dismutase; SUV39H1, Histone-lysine N-methyltransferase; SREBP, Sterol regulatory elementbinding protein; TNF, tumor necrosis factor.

Although HDAC enzymes are promising drug targets because of their importance in cell cycle regulation, proliferation, differentiation, metabolism, protein trafficking and DNA repair, currently available HDAC inhibitors are mostly non-

selective (pan-HDAC inhibitors). Thus the effects of HDAC inhibitors are often studied by examining changes in bulk histone acetylation or the therapeutic effects observed in a given experimental model or in clinical trails. Consequently, it

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is important to develop more specific inhibitors of individual HDAC isoforms that are critically involved in particular processes to improve their efficacy and reduce toxicity. Recent studies have provided some promising results for more selective HDAC inhibitors. For instance, compounds containing aryl substitutions on the benzamide warhead have been found to be highly selective for HDACs 1 and 219–21. SNDX-275 (Syndax Pharmaceutical Inc.) is a synthetic benzamide derivative with activity against HDACs 1, 2 and 3 (class I) in the mM range. Similarly, a series of apicidin-based alkyl ketones appear to be selective for HDACs 1, 2 and 322–24. MGCD0103 (Methylgene Inc.) is an isoform-selective aminophenylbenzamide that inhibits HDACs of classes I and IV with almost no effect on those of class II. Tubacin and TSA exhibit greater selectivity for HDAC625–28.

4.

HDAC and glucose homeostasis

Glucose homeostasis is maintained through tight regulation of glucose production in the liver and glucose uptake in the peripheral tissues particularly skeletal muscle and adipose tissue. Insulin and glucagon play critical roles in this regulation29. In the fed state, insulin signals lower blood glucose by facilitating glucose uptake mainly into peripheral tissues and by inhibiting endogenous glucose production in the liver30. Conversely, in the fasted state, glucagon signals up-regulate gluconeogenesis and the breakdown of glycogen in the liver. In terms of mechanism, insulin activates the serine/threonine kinase Akt which, in turn, activates the glucose transporter 4 (GLUT4) to translocate from intracellular vesicles to the plasma membrane where it facilitates glucose uptake31. The activation of Akt is also known to suppress the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-

phosphatase (G-6-Pase), the rate-controlling gluconeogenetic enzymes32. It does this by phosphorylating foxhead box O1 (FOXO1), thus repressing the transcription of the PEPCK and G-6-Pase genes33. In contrast, glucagon is known to increase hepatic gluconeogenesis by inducing the expression of PEPCK and G-6-Pase, the regulation of which requires co-activators such as peroxisome proliferator-activated receptor g co-activator 1a (PGC-1a) and cAMP response element-binding (CREB) protein34. Recent studies indicate that the regulation of glucose homeostasis is associated with epigenetic mechanisms. Posttranslational modifications of histones by acetylation, phosphorylation, methylation and ubiquitination play important roles in gene transcription35. In particular, acetylation of histone and non-histone proteins provides a key mechanism for controlling cellular signaling and gene expression. The HDACs regulate this acetylation of histone and transcriptional factors which are involved in glucose homeostasis and play a central role in the regulation of glucose metabolism. The functions of HDACs in the regulation of glucose homeostasis are illustrated in Fig. 1.

4.1.

HDAC and insulin resistance

As previously stated, insulin signals play an important role in regulating blood glucose by promoting glucose uptake in peripheral tissues and decreasing glucose production and stimulating glycogen synthesis in the liver. Once insulin binds to its receptor, phosphate groups are added to tyrosines on particular proteins in the cell including insulin receptor substrate (IRS) 1. This then activates PI3K which, in turn, phosphorylates the protein kinase Akt which is important for the stimulation of GLUT4 expression.

Figure 1 The role of HDACs in the regulation of glucose metabolism. (A) HDACs down-regulate the expression of GLUT4 and promote insulin resistance in adipocytes and muscle cells. (B) HDAC1 reduces the expression of PDX1 leading to the decreased expression of insulin while SIRT1 up-regulates UCP2 which promotes the secretion of insulin. (C) HDACs are involved in the regulation of gluconeogenesis in hepatocytes in several ways: in the stimulation of glucagon, class IIa HDACs are dephosphorylated and translocated from the cytoplasm to the nucleus; class IIa HDACs recruit HDAC3 which can deacetylate FOXO1 and FOXO3 thereby enhancing FOXO DNA-binding to promote gluconeogenetic gene expression; ER stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via HDAC-dependent STAT3 deacetylation.

Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications in diabetes mellitus It has been shown that HDACs play a regulatory role in insulin signalling. Recent reports indicate that HDAC2 can bind to IRS-1 in liver cells of the db/db mouse, leading to decreased acetylation and reduced insulin receptor-mediated tyrosine phosphorylation of IRS-1. Accordingly, the HDAC inhibitor TSA or gene silencing of HDAC2 enhance acetylation of IRS-1 and partially attenuate insulin resistance36. GLUT4 is important for glucose uptake as indicated by the fact that insulin-dependent glucose homeostasis is sensitive to changes in GLUT4 expression and translocation37–39. The GLUT4 gene promoter is governed by two domains namely the MEF2 binding domain and Domain I. When MEF2 binds to the MEF2 binding domain and GLUT4 enhancer factor (GEF) binds to Domain I, transcriptional activity is the most advanced40–43. It has been suggested that class II HDACs down-regulate MEF2-dependent gene transcription. Some studies also report that activation of HDAC5 decreases GLUT4 expression in cardiac tissue and that a decrease in HDAC5 activity correlates with an increase in GLUT4 expression during exercise44. Chromatin immunoprecipitation (ChIP) assays also demonstrate that HDAC5 is associated with the GLUT4 promoter in preadipocytes45 where, through analysis by in vitro transcription assays, it has been shown that HDAC5 specifically represses transcriptional activation of the GLUT4 promoter. After HDAC5 undergoes complex formation with GEF and MEF2, controlled by its phosphorylation via AMP-activated protein kinase (AMPK) and calmodulindependent protein kinase (CaMK), HDAC5 deacetylates histone and compacts the chromatin structure leading to repression of GLUT4. Recent studies also provide strong evidence of the importance of HDAC6 in glucocorticoid receptor-mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. For example, impaired dexamethasone-induced hepatic glucocorticoid receptor translocation has been found in HDAC6 knockout mice. In fact, dexamethasone-induced expression of some hepatic genes is markedly attenuated in these mice and significant improvements in dexamethasone-induced whole-body glucose intolerance and insulin resistance is observed indicating that HDAC6 is an essential regulator of insulin signaling46.

4.2.

HDAC and insulin expression and secretion

HDACs have been demonstrated to down-regulate pancreatic insulin formation and secretion47,48. Insulin gene expression is up-regulated at higher glucose concentrations and is associated with several transcription factors including duodenal homeobox 1 (PDX1)48, V-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA)49,50 and neurogenic differentiation 1 (NeuroD1)51. Expression and release of insulin is regulated by the acetylation status of histone H447. The transcription factor PDX1, specific to pancreatic b-cells, interacts with the p300 transcriptional co-activator to enhance proinsulin expression48. Some studies indicate that HDAC1 is involved in silencing PDX1 leading to failure in b-cell development and to b-cell dysfunction52. Although some studies also report that transcription factors such as NeuroD153 and MafA49,50 are associated with acetylation states that lead to increased binding activity, whether HDACs actually regulate this association remains unclear.

391

In contrast, a report from Moynihan et al.54 has demonstrated that SIRT1 improves glucose-induced pancreatic insulin secretion. In their study, transgenic mice selectively overexpressing SIRT1 in pancreatic b-cells (BESTO mice) showed improved glucose tolerance and enhanced insulin secretion in response to glucose. Furthermore, microarray analyses of b-cell lines revealed that SIRT1 regulated genes, including uncoupling protein 2 (UCP2), are involved in insulin secretion. These results indicate for the first time that SIRT1 is important in b-cell function in vivo and has potential as a target in treating type 2 diabetes. 4.3.

HDAC and gluconeogenesis

Gluconeogenesis is another important process in glucose homeostasis that is reportedly regulated by HDACs. This is through the control of the activity of FOXO transcription factors which are critical for mediating the expression of gluconeogenetic ratelimiting genes including those expressing G-6-Pase and PEPCK. HDAC1 induces the expression of hepatocyte nuclear factor 4a (HNF4a) and the dephosphorylation of FOXO1 in hepatocytes leading to the induction of PEPCK expression and gluconeogenesis in the liver55. Moreover, some studies have found that class IIa HDACs regulate glucagon-induced FOXO activation and that AMPK and salt-inducible kinases (SIKs) 1 and 2 can phosphorylate class IIa HDACs (HDAC4, 5 and 7) which are then excluded from the nucleus. Under stimulation from the fasting hormone, glucagon, class IIa HDACs are rapidly dephosphorylated and translocated from the cytoplasm to the nucleus where they recruit and form a complex with HDAC3 which has the ability to deacetylate FOXO1 and FOXO3a. This enhances FOXO DNA-binding which regulates gluconeogenetic gene promoters such as that of G-6-Pase. The recruitment of HDAC3 also results in the acute transcriptional induction of gluconeogenetic genes via deacetylation and activation of FOXO family transcription factors. Loss of class IIa HDACs inhibits FOXO targeted gluconeogenetic genes and lowers blood glucose leading to increased glycogen storage. In mouse models of type 2 diabetes, inhibition of class IIa HDACs has been further shown to ameliorate hyperglycemia, indicating that class IIa HDACs regulate G-6-Pase expression and subsequently affect gluconeogenesis56. HDACs have also been shown to be involved in signal transducer and activator of transcription 3 (STAT3)-mediated gluconeogenesis57. STAT3 can be acetylated by CREB protein/p300 and deacetylated by HDACs58. In the liver, STAT3 plays an important role in the suppression of gluconeogenic enzyme expression. The study by Kimura et al.57 reveals that endoplasmic reticulum (ER) stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via Janus kinase 2 (JAK2) dephosphorylation and HDAC-dependent STAT3 deacetylation demonstrating the importance of HDACs in mediating the increase in hepatic glucose production that occurs in obesity and diabetes. However, the particular HDAC isoforms involved in the deacetylation of STAT-3 remains unknown. 5.

HDAC inhibition in the treatment of diabetic complications

The evidence reviewed here indicates that HDACs are involved in the pathogenesis of diabetes mellitus through

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regulating glucose homeostasis via a number of pathways. In addition, many large scale clinical studies of diabetes have demonstrated that early intensive glycemic control reduces the incidence and progression of micro and macrovasular complications. However, epidemiological and prospective data reveal that the stressors in the diabetic vasculature persist beyond the point when glycemic control is achieved. In fact, the detrimental effects that result from the development and progression of the complications of hyperglycemia can persist for years. Fortunately, in addition to regulate glucose metabolism by increasing insulin secretion, improving insulin resistance and controlling gluconeogenesis, HDAC inhibitors also show promise in the treatment of diabetic complications including diabetic nephropathy (DN)59,60 and diabetic retinopathy (DR)61,62. The efficacy of HDAC inhibitors in treating these conditions appears to be governed by multiple actions on a variety of pathophysiological processes as shown in Fig. 2.

5.1.

HDAC and diabetic nephropathy

DN is one of the major microvascular complications of diabetes and the most common cause of end-stage renal disease (ESRD)63. Although the pathogenesis of DN is multifactorial, recent clinical trials and experimental studies have highlighted the importance of HDAC-mediated epigenetic processes in its development. HDAC inhibitors have been reported to have an antifibrotic effect in the kidney64. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells and excessive accumulation of extracellular matrix (ECM) in the kidney contribute to the renal fibrosis in DN. It has been reported that inhibition

of HDAC activity suppresses the EMT induced by TGF-b1 in human renal epithelial cells58. HDAC inhibitors can induce the expression of DNA binding/differentiation 2 (Id2) and bone-morphogenic protein (BMP)-7 to inhibit TGF-b1 signalling64. Further studies demonstrate that the HDAC inhibitor, TSA, prevents TGF-b1-induced apoptosis by inhibiting TGFb1-induced extracellular signal-regulated kinase (ERK) activation. Furthermore, recent studies report that TSA decreases mRNA and protein expression of the components of ECM and prevents the EMT in streptozotocin (STZ)-induced diabetic kidneys. In addition, it has been found that HDAC2 activity is significantly increased in the kidney of STZ-induced diabetic rats and db/db mice as well as in TGF-b1-treated normal rat kidney tubular epithelial cells60. HDAC2 knockdown reduces fibronectin and a-smooth muscle actin expression but increases E-cadherin expression suggesting that it plays an important role in the accumulation of ECM and the EMT in diabetic kidney. Very recently, a study has revealed that long-term treatment with vorinostat improves albuminuria and mesangial matrix accumulation in diabetic mice through an endothelial nitric oxide synthase (eNOS)-dependent mechanism65. This finding provides further evidence to support the potential utility of HDAC inhibitors in the treatment of cardiorenal diseases. Our recent studies also show that, among the Zn2þ-dependent HDACs, class II HDACs 4 and 5 are significantly increased both in vivo and in vitro in kidneys exposed, to high glucose concentrations which are associated with NADPH oxidase-mediated oxidative stress (unpublished data). One of the earliest features of DN is renal enlargement. Epidermal growth factor (EGF) plays a pivotal role in the development of diabetic nephromegaly and transactivation of

Figure 2 Summary of the mechanisms by which HDACs induce diabetic nephropathy and retinopathy.

Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications in diabetes mellitus

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its receptor has been implicated in the pathogenesis of laterstage disease. Vorinostat has been found to attenuate early renal enlargement in experimental diabetes, an effect probably mediated, at least in part, by down-regulation of the EGFR and attenuation of EGF-mediated tubular epithelial cell proliferation66.

Foundation of China (81170772, 81070918, 81171062 and 30901551); the Shandong Natural Science Fund for Distinguished Young Scholars to Yi F (JQ201121); the Independent Innovation Foundation of Shandong University (IIFSDU2010JC17); and the Nature Science Foundation of Shandong Province (ZR2010HM112).

5.2.

References

HDAC and diabetic retinopathy

DR presenting as macular edema and proliferative retinopathy is considered the most sight-threatening ocular complication in diabetic patients but its exact pathogenesis remains unclear. A report from Zhong and Kowluru62 indicates that, in STZinduced diabetic rats, the expressions of HDACs 1, 2 and 8 are significantly increased in retinal tissue and cells derived from it. As a result, the activity of HAT is compromised and the acetylation of histone H3 is decreased62. Retinal ischemia plays an important role in DR and may involve necrotic and apoptotic processes. A variety of cellular events are also thought to contribute to the degenerative response in diabetic patients. It has been reported that TSA administration produces a significant anti-inflammatory effect in the retina associated with the suppression of retinal tumor necrosis factor-a (TNF-a) expression and inhibition of MMPs. Valproic acid (VPA) can also protect the retina from ischemia through the endoplasmic reticulum (ER) stress pathway. VPA significantly increases the expression of glucose-regulated protein (GRP) 78, which may result from the hyperacetylation of histone H3. GRP78 forms a complex with caspase-7 and -12 to prevent the release of caspase-12 from the ER, thereby inhibiting ER stressinduced caspase activation67. In this way ER stress induced apoptosis can be ameliorated by treatment with VPA68. 6.

Conclusions and perspectives

This review provides evidence that supports the role of HDACs in diabetes mellitus and outlines several important cellular and molecular mechanisms for the regulation of glucose homeostasis. It also describes the targeting of HDACs for the treatment of diabetic complications through the regulation of insulin resistance and secretion. Due to space limitations, the possible roles of HDACs in inflammation and the immunoresponse in diabetes mellitus are not included but have been comprehensively reviewed elsewhere69. Taken together, the evidence provides a strong rationale to continue preclinical studies and initiate clinical trials of HDAC inhibitors. However, prolonged broadspectrum HDAC inhibition using the currently available panHDAC inhibitors involves risk not only because these substances are associated with adverse side effects, but also because little is known about the function of individual HDACs in diabetes mellitus. In further researching the clinical use of HDAC inhibitors, it will be important to elucidate the role of individual HDACs within the body and to develop HDAC inhibitors with improved specificity to provide an effective therapeutic strategy for the treatment of diabetes mellitus. Acknowledgments The authors wish to thank the following for financial support for this study: the National 973 Basic Research Program of China (2012CB517700); the National Nature Science

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