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
b
Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

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

KEY WORDS Abstract Epigenetic mechanisms such as DNA methylation, histone modification and microRNA
Histone deacetylases;
changes have been shown to be important for the regulation of cellular functions. Among them,
Diabetes mellitus; histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone
Histone acetyltrans- acetyltransferases in chromatin remodeling and play essential roles in gene transcription to regulate
ferases; cell proliferation, migration and death. Recent studies indicate that HDACs are promising drug
HDAC proteins; targets for a wide range of diseases including cancer, neurodegenerative and psychiatric disorders,
HDAC inhibitors 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
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n
Corresponding author. Tel./fax: þ86 0531 88382616.
E-mail address: fanyi@sdu.edu.cn (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. 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 tran-
scription to regulate cell proliferation, migration and apopto-
sis, 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 treat-
ment of cancer. Recent studies also indicate that targeting
HDACs is a promising therapeutic strategy for a number of
other diseases including neurodegenerative disorders, cardio-
vascular 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 inhibi-
tors 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 subdi-
vided into class IIa (HDAC4, 5, 7, 9) and IIb (HDAC6, 10)
with class IIa having relatively low enzymatic activity com-
pared 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
Xiaojie Wang et al.
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 modifica-
tion by acetylation or ADP-ribosylation. Among them, SIRT1
and SIRT2 can shuttle between the nucleus and cyto-
plasm12,13. 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 posi-
tively 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 pro-
mote ammonia detoxification. SIRTs 6 and 7 are predomi-
nantly 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, cardio-
vascular 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, loca-
tion, substrates, main biological functions and inhibitors of
HDACs are shown in Table 1.
3. HDAC inhibitors
HDAC inhibitors are chemical compounds that inhibit Zn2þ-
dependent 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 hydro-
xamates, cyclic peptides, aliphatic acids, benzamides, boronic
acid-based compounds, benzofuranone and sulfonamide con-
taining 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 389

Table 1 The HDAC family: classification, localization and substrates.

HDAC Location Substrates Biological functions Main HDAC

inhibitor
Class Member

I HDAC1 Nucleus Histones, MEF2, GATA, YY1, NF-kB, Cell survival and proliferation Valproic acid,
DNMT1–SHP, ATM, MyoD, p53, AR, vorinostat, TSA,
BRCA1, MECP2, pRb RGFP1-36
HDAC2 Nucleus Histones, HOP, NF-kB, GATA2, Insulin resistance; cell (HDAC3)
BRCA1, pRb, MECP IRS-1 proliferation
HDAC3 Nucleus Histones, HDAC4, 5, 7–9, SHP, Cell survival and
GATA1, NF-kB, pRb proliferation
HDAC8 Nucleus HSP70 Cell proliferation
IIa HDAC4 Nucleocytoplasmic Histones, SRF, Runx2, p53, p21, GATA, Regulation of skeletogenesis TSA, vorinostat,
traffic FOXO, HIF-1a, SUV39H1, HP1, HDAC3, and gluconeogenesis phenylbutyrate
MEF2, CaM, 14-3-3
HDAC5 Nucleocytoplasmic Histones, HDAC3, YY1, MEF2, Cardiovascular growth and
traffic Runx2, CaM, 14-3-3 function; cardiac myocytes
and endothelial cell function;
gluconeogenesis
HDAC7 Nucleocytoplasmic Histones, HDAC3, MEF2, PML, Thymocyte differentiation–
traffic Runx2, CaM, 14-3-3, HIF-1a endothelial function–
gluconeogenesis
HDAC9 Nucleus Histones, HDAC3, MEF2, CaM, Thymocyte differentiation;
14-3-3 cardiovascular growth and
function
IIb HDAC6 Cytoplasm a-tubulin, Cortactin, HSP90, HDAC11, Cell motility–control of Vorinostat,
SHP, PP1, Runx2, LcoR cytoskeletal dynamics TSA, tubacin
HDAC10 Nucleocytoplasmic LcoR, PP1 Homologous recombination (HDAC6)
traffic
III SIRT1 Nucleus Histones, p53, p73, p300, NF-kB–FOXO, Aging; redox control–cell Nicotinamide
PTEN, NICD, MEF2, HIFs, SREBP-1c, b- survival–autoimmune system (SIRT1),
catenin, PGC1a, Bmal, NF-kB, Per2, Ku70, regulation suramin (SIRT1
XPA, SMAD7, Cortactin, Ku70, IRS-2, and SIRT2)
APE1, PCAF, TIP60, p300, AceCS1,
PPARg, ER-a, AR, LXR
SIRT2 Nucleus Histones, a-tubulin Cell survival–cell migration
and invasion
SIRT3 Mitochondria Histones, Ku70, IDH2, HMGCS2, GDH, Redox control
AceCS, SdhA, SOD2, LCAD
SIRT4 Mitochondria GDH Enegry metabolism
SIRT5 Mitochondria Cytochrome c, CPS1 Urea cycle
SIRT6 Nucleus Histone H3, TNF-a Metabolic regulation
SIRT7 Nucleus p53 Apoptosis
IV HDAC11 Nucleus Histones, HDAC6, Cdt1 Immunomodulators–DNA Sodium
replication 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, Hydroxymethyl-
glutaryl-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-domain-
containing phosphatase; SOD, Superoxide dismutase; SUV39H1, Histone-lysine N-methyltransferase; SREBP, Sterol regulatory element-
binding protein; TNF, tumor necrosis factor.

Although HDAC enzymes are promising drug targets selective (pan-HDAC inhibitors). Thus the effects of HDAC
because of their importance in cell cycle regulation, prolifera- inhibitors are often studied by examining changes in bulk
tion, differentiation, metabolism, protein trafficking and DNA histone acetylation or the therapeutic effects observed in a
repair, currently available HDAC inhibitors are mostly non- given experimental model or in clinical trails. Consequently, it
390 Xiaojie Wang et al.

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 benza-
mide 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 amino-
phenylbenzamide 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 regula-
tion29. 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/threo-
nine kinase Akt which, in turn, activates the glucose trans-
porter 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-acti-
vator 1a (PGC-1a) and cAMP response element-binding
(CREB) protein34.
Recent studies indicate that the regulation of glucose
homeostasis is associated with epigenetic mechanisms. Post-
translational modifications of histones by acetylation, phos-
phorylation, 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 transcrip-
tional 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 home-
ostasis 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 acetyla-
tion 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 forma-
tion with GEF and MEF2, controlled by its phosphorylation
via AMP-activated protein kinase (AMPK) and calmodulin-
dependent protein kinase (CaMK), HDAC5 deacetylates
histone and compacts the chromatin structure leading to
repression of GLUT4.
Recent studies also provide strong evidence of the impor-
tance 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 recep-
tor 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 improve-
ments in dexamethasone-induced whole-body glucose intoler-
ance 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 asso-
ciated with several transcription factors including duodenal
homeobox 1 (PDX1)48, V-maf musculoaponeurotic fibrosar-
coma 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 devel-
opment 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 demon-
strated that SIRT1 improves glucose-induced pancreatic insu-
lin 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 home-
ostasis 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 rate-
limiting 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 gluconeo-
genesis 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 gluconeoge-
netic 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 pro-
tein/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 produc-
tion 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
392
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 compli-
cations. 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 detri-
mental effects that result from the development and progres-
sion 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 multi-
factorial, 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 accumu-
lation of extracellular matrix (ECM) in the kidney contribute
to the renal fibrosis in DN. It has been reported that inhibition
Figure 2 Summary of the mechanisms by which HDACs induce diabetic nephropathy and retinopathy.
Xiaojie Wang et al.
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 signal-
ling64. Further studies demonstrate that the HDAC inhibitor,
TSA, prevents TGF-b1-induced apoptosis by inhibiting TGF-
b1-induced extracellular signal-regulated kinase (ERK) activa-
tion. 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 oxida-
tive 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
Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications in diabetes mellitus
its receptor has been implicated in the pathogenesis of later-
stage 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.
5.2. 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 STZ-
induced 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 stress-
induced 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 resis-
tance 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 broad-
spectrum HDAC inhibition using the currently available pan-
HDAC 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
393
Foundation of China (81170772, 81070918, 81171062 and
30901551); the Shandong Natural Science Fund for Distin-
guished Young Scholars to Yi F (JQ201121); the Independent
Innovation Foundation of Shandong University (IIFS-
DU2010JC17); and the Nature Science Foundation of Shan-
dong Province (ZR2010HM112).
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