Histone Deacetylase Inhibitors: A Promising Therapeutic Alternative for Endometrial Carcinoma

Abstract

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest, differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase, histone deacetylase inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising therapeutic agents in the treatment of patients with endometrial cancer.

Full text

Review Article
Histone Deacetylase Inhibitors: A Promising Therapeutic
Alternative for Endometrial Carcinoma
Iason Psilopatis ,
1,2
Alexandros Pergaris ,
1
Constantinos Giaginis ,
3
and Stamatios Theocharis
1
1
First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Bld 10,
Goudi, 11527 Athens, Greece
2
Charité-University School of Medicine, Augustenburger Pl. 1, 13353 Berlin, Germany
3
Department of Food Science and Nutrition, University of Aegean, Lemnos, Greece
Correspondence should be addressed to Stamatios Theocharis; stamtheo@med.uoa.gr
Received 18 August 2021; Revised 19 October 2021; Accepted 30 October 2021; Published 12 November 2021
Academic Editor: Kristina W. Thiel
Copyright © 2021 Iason Psilopatis et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic
alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class
of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest,
differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the
therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature
review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase,histone deacetylase
inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial
carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both
endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and
decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced
physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The
combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in
endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and
progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as
tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising
therapeutic agents in the treatment of patients with endometrial cancer.
1. Introduction
The nucleosome is the building block of DNA structural orga-
nization and enables the necessary packaging of the genetic
material in a denser form fitting within the eukaryotic nucleus.
It refers to a negatively charged DNA strand wrapped around
a positively charged histone octamer, a protein core consisting
of two identical copies of each of the four core histone proteins
(H2A, H2B, H3, and H4) [1, 2]. In this condensed formation,
histones have low levels ofacetylation on the lysine residues of
their aminoterminal tails, thus blocking the assembly of the
basal transcriptional factors to form the preinitiation complex
that allows genetic expression [3, 4]. The post-translational
modification of the NH2-terminal tails of histones by acetyla-
tion neutralizes the positive charge on lysine residues and
reduces the affinity of histone for the negatively charged
DNA. As such, DNA strands may uncoil and transcription
may occur [5]. The level of histone acetylation is modulated
by the opposing actions of histone acetylases (HATs) and his-
tone deacetylases (HDACs) [6]. HDACs catalyze the removal
of acetyl groups on the NH2-terminal lysine residues of core
nucleosomal histones, which generally results in transcriptional
Hindawi
Disease Markers
Volume 2021, Article ID 7850688, 9 pages
https://doi.org/10.1155/2021/7850688

repression and silencing of tumor-suppressor genes [7, 8].
Consequently, deregulation of histone acetylation can pro-
mote the development of certain human cancers, as shown
by a great number of researchers who focused on revealing
the link between histone acetylation/deacetylation and carci-
nogenesis [9, 10].
Endometrial carcinoma (EC) is the most common malig-
nant tumor of the female genital tract in the United States.
According to the American Cancer Society, about 66,570
new cases of cancer of the body of the uterus will be diagnosed
and about 12,940 women will die from cancers of the uterine
body in the United States in 2021 [11]. EC primarily affects
postmenopausal women aged 55-64, with the median age at
diagnosis being 63 years [12]. ECs can be divided into two
distinct histopathologic subgroups: type I EC deriving from
atypical endometrial hyperplasia and type II EC of non-
endometrioid histology [13]. Type I EC is directly related to
long-term exposure to increased estrogen levels and is associ-
ated with PTEN inactivation by mutation, microsatellite insta-
bility, and mutations of K-ras,β-catenin,orhMLH1/MSH2.
Type II EC is mostly estrogen-independent, develops from
atrophic endometrium in postmenopausal women, and is
characterized by p53 mutations, display inactivation of p16
and E-cadherin, as well as Her2/neu amplification [14, 15].
While surgery is recommended as a monotherapy for low-
risk ECs, adjuvant chemotherapy should be offered to women
with high-intermediate- and high-risk ECs, as well as advanced
or recurrent disease [16]. Combined chemotherapy with carbo-
platin and paclitaxel is the first-line regimen, followed by
chemotherapeutic agents such as doxorubicin, cyclophospha-
mide, or cisplatin [17].
Despite the reported high response rates, the duration of
response is only short-lasting, ranging from between four and
eight months [18] and 5-year overall survival amounting to
81%, according to the American Cancer Society [19]. However,
prognosis for patients with advanced disease remains grim,
with 5-year survival rates dropping to 17% when distant metas-
tasis is present [19]. Such statistics render imperative the devel-
opment of innovative agents for the effective treatment of EC.
Histone deacetylase inhibitors (HDACIs) are a novel class
of anticancer drugs that increase the level of histone acetyla-
tion in many cell types, thereby inducing cell cycle arrest,
differentiation, and apoptotic cell death, thus suppressing
carcinogenesis [20, 21] (Figure 1). Few HDACIs have already
received FDA approval for T-cell lymphoma or multiple mye-
loma, yet there is a great number of current clinical trials
investigating the role of HDACIs (alone or in combination
with other anticancer drugs) in the treatment of numerous
solid cancer entities [22, 23]. Given the genetic alternations
in EC, HDACIs could be considered promising therapeutic
agents.
1.1. Histone-Mediated Epigenetics in EC Clinical Samples and
Cell Lines. Histone-mediated epigenetics plays an established
role in EC development and progression. A large number of
studies have assessed the genetic alternations associated with
histone-mediated epigenetics in population-based cohorts of
EC tumor types [15, 24–31] (Table 1).
Histone acetylation is involved in the silencing of human
mutL homolog 1 (hMLH1)/mutS homolog 2 (MSH2), phos-
phatase and tensin homolog (PTEN), and progesterone
receptor (PR), thus resulting in early carcinogenesis, more
aggressive carcinomas, and resistance to hormonal treatment,
respectively [15]. Specifically, silencing of hMLH1 and/or
MSH2 causes microsatellite instability, invasive growth, and
acquired resistance to cisplatin in EC [24]. Class I HDACs
(HDAC1, HDAC2, and HDAC3) are expressed in the major-
ity of ECs at high levels, with high-grade serous subtypes
exhibiting overexpression of all three HDACs significantly
more often than endometrioid subtypes [25]. Notably,
HDAC2 overexpression has been suggested to be involved in
the acquisition of aggressive behavior by EC [26]. Krusche
et al. reported that, compared to normal endometrium, many
ECs showed impaired HDAC1 protein expression in the
epithelial and stromal compartment, which might be indicative
of an impaired epigenetic status of epithelial and stromal cells
within ECs [27]. HDAC6, modulated by miR-206, promotes
EC progression through the PTEN/AKT/mTOR pathway
[28]. Deregulating E-cadherin correlates with focal adhesion
kinase (FAK) signaling axis and HDAC/enhancer of zeste
homolog 2 (EZH2) activity. EZH2, FAK, and phospho-FAK
(pFAK) overexpression is mainly identified in type II ECs and
is associated with worse prognosis and decreased overall sur-
vival [29]. Low forkhead box A1 (FOXA1) protein expression
significantly correlates with high-grade carcinoma, loss of estro-
gen receptor α(ERα) and PR, and poor survival [30]. The
bromodomain-containing gene ATPase family AAA domain
containing 2 (ATAD2) is a mediator of MYC transcriptional
function and represents a marker of aggressive ECs [31].
Several in vitro studies have examined the role of
histone-mediated epigenetics in EC cell lines as well.
Mitogen-inducible gene 6 (MIG6) mRNA levels are
lower in cell lines derived from high-grade ECs than in
low-grade EC cell lines. MIG6 is an essential downstream
component of PR-mediated growth suppression [32]. Aber-
rant expression of miRNAs including miR-200b, miR130a/b,
miR-625, and miR-222 is associated with tumorigenesis and
metastasis in EC cell lines [33].
All of the aforementioned genetic alternations in ECs are
strongly influenced by histone-mediated epigenetics.
1.2. In Vitro Effects of HDACIs on EC Cell Lines. There are
five identified classes of HDACIs including organic hydroxa-
mic acids, short-chain fatty acids, benzamides, cyclic tetra-
peptides, and sulfonamide anilides [14, 34]. Different
in vitro studies have investigated the effects of various HDA-
CIs on genetic alternations in EC cell lines associated with
histone-mediated epigenetics (Table 2). The reported HDA-
CIs seem to have a profound effect on cell viability by inhi-
bitingcell proliferation and inducing cell death in EC. The
specific chemical structures of HDACIs used in EC-related
studies are depicted in Figure 2.
Apicidin. Apicidin is a fungal metabolite shown to exert
antiparasitic activity by the inhibition of HDAC [35]. In EC
cell lines, Apicidin results in the upregulation of acetylated
H3 and H4, p21, p27, and E-cadherin and the downregula-
tion of cyclin A, cyclin D1, cyclin E, CDK2, CDK4, p53,
2 Disease Markers

HDAC3, and HDAC4. As a result, Apicidin induces morpho-
logical changes, increases the proportion of cells in the G1
phase, and decreases the number of cells in the S phase [18,
36, 37]. Moreover, Apicidin increases the level of PARP cleav-
age and caspase-3 activity, induces cytoplasmic localization of
cytochromec, and causes the downregulation ofthe antiapop-
totic gene, Bcl-2, and upregulation of the proapoptotic gene,
Bax, thus inducing apoptotic cell death [18, 36]. Concerning
estrogen-dependent cancers, Apicidin suppresses transcrip-
tion of 17β-hydroxy steroid dehydrogenase type 1 in EC cells,
which is responsible for intratumoral estrone to 17βestradiol
conversion [38].
Trichostatin A (TSA). TSA, an antifungal antibiotic initially
isolated from Streptomyces hygroscopicus, is a potent and spe-
cific HDACI [39]. TSA increases the levels of acetyl H3, acetyl
H4, acetyl tubulin, p21, p27, miR-130b, DICER1, BIM,
L1CAM, FOXA1, glycodelin, and E-cadherin and decreases
the levels of cyclin A, cyclin D1 and D2, MMP2, MMP9,
G0 phase
G1
G2S
M
Cell cycle arrest
Dierentiation
Upregulation of tumor
suppressor genes and PR
Neoangiogenesis
(through VEGF downregulation)
Cell proliferation and
tumor growth
Transcription of oncomirRs
(miR-200b, miR-130a/b,
miR-625, miR-222)
Mitosis
(through MIG6 upregulation) Apoptosis
HDACs
HDAC inhibitors
(resting)
Figure 1: HDAC inhibitors exert their tumor-suppressive role through various mechanisms. Green arrows: procedures enhanced by HDAC
inhibitors. Red arrows: procedures blocked by HDAC inhibitors (created with http://Biorender.com). HDAC: histone deacetylase; PR:
progesterone receptor; MIG6: mitogen-inducible gene 6; VEGF: vascular endothelial growth factor.
Table 1: Genetic alternations in ECs associated with histone-mediated epigenetics.
Genetic alternations in ECs Impact on EC development and progression Reference
Silencing of hMLH1/MSH2, PTEN, and PR Early carcinogenesis, more aggressive carcinomas, resistance to hormonal
treatment [15]
Silencing of hMLH1 and/or MSH2 Microsatellite instability, invasive growth, acquired resistance to cisplatin [24]
Overexpression of class I HDACs Significantly more often in high-grade serous subtypes [25]
Overexpression of HDAC2 Acquisition of aggressive behavior [26]
Impaired HDAC1 protein expression Impaired epigenetic status of epithelial and stromal cells [27]
miR-206 modulation of HDAC6 Progression through the PTEN/AKT/mTOR pathway [28]
Overexpression of EZH2, FAK, and pFAK Worse prognosis, decreased overall survival [29]
Low FOXA1 protein expression High-grade carcinomas, loss of ERαand PR, poor survival [30]
ATAD2 expression Aggressive carcinomas [31]
Low MIG6 mRNA levels High-grade carcinomas, failure of PR-mediated growth suppression [32]
Aberrant expression of miRNAs Tumorigenesis, metastasis [33]
3Disease Markers

Table 2: In vitro effects of HDACIs on EC cell lines.
HDACI Upregulatory effects Downregulatory effects Synergetic effects References
Apicidin Acetylated H3 and H4, p21, p27,
E-cadherin, PARP, caspase-3, cytochrome c, Bax
Cyclin A, cyclin D1, cyclin E, CDK2,
CDK4, p53, HDAC3,
HDAC4, Bcl-2, 17β-hydroxysteroid-dehydrogenase
type 1
n/a [18, 36–38]
TSA
Acetylated H3, H4, and tubulin, p21, p27, miR-
130b, DICER1, BIM, L1CAM, FOXA1, glycodelin,
E-cadherin, PARP, caspase-3
Cyclin A, cyclin D1 and D2, MMP2,
MMP9, DNMT3B mRNA, ERα,
MCM7 mRNA, MYC,
miR-106b-93-25
Aza-deoxycytidine: PR-B upregulation
High-glucose condition: degradation of
CLDN-2
Paclitaxel: cell death induction
[26, 30, 31, 33,
40–50]
SAHA
Acetylated H3 and H4 bound to either Tig1 or C/
ebpa gene, caspase-8 and caspase-9, glycodelin,
FOXA1, E-cadherin, p21, p27, insulin-like growth
factor-I receptor
Cyclin D1 and D2, Bcl-2, FLIP mRNA and protein
levels, AURKA n/a [30, 40, 41, 53–58]
LBH589 PR mRNA, MIG6 MYC
Death receptor ligand TRAIL: cell
death induction after knockdown of
metadherin
Proteasome: overcomes the impact of
gain-of-function p53 mutations
[32, 60–63]
NaB Acetylated H3 and H4, p21, p27, ROS, phospho-
p38 mitogen-activated protein kinase, γH2AX ERαAdriamycin: high human telomerase
reverse transcriptase expression [41, 42, 65–68]
VPA E-cadherin Bcl-2 VE465: PARP cleavage induction [56, 70, 71]
OBP-801/YM753 n/a n/a LY294002: BIM increase with
accumulation of ROS [72]
Oxamflatin PARP, caspase-8 and caspase-9 n/a n/a [15]
Scriptaid Acetylated H3 and H4, p21, p27, E-cadherin Cyclin A, Bcl-2 n/a [75]
FK228 Acetylated H3 and H4, p21, p53, caspase-3,
caspase-7, and caspase-8, PARP n/a n/a [77]
PsA Acetylated H3 and H4, p21 p53, pRb, cyclins, CDKs n/a [78]
MHY2256 p53 SIRT1 enzyme activity, SIRT protein levels, MDM2 n/a [79]
4 Disease Markers

DNMT3B mRNA, ERα, and MCM7 mRNA [26, 30, 33,
40–46]. After treatment with TSA, cleavage of PARP and
caspase-3 was observed, indicating its apoptotic effects [26,
46]. TSA inhibits cell proliferation by arrest in the G1 and/or
G2 phases of the cell cycle [33, 46]. Raeder et al. suggested that
dependency on MYC predicts dependency on ATAD2 and
response to TSA in EC [31], while Zhao et al. demonstrated that
the downregulation of MYC in the presence of TSA resulted in
the reduction of miR-106b-93-25 cluster [46]. TSA acts syner-
gistically with aza-deoxycytidine and results in a robust and sus-
tainable PR-B upregulation [47]. High-glucose condition and
TSA induce degradation of CLDN-2 in Sawano cells [48].
TSA in combination with paclitaxel induces synergistic cell
death, results in significant morphologic changes, induces
activation of the intrinsic mitochondria-dependent apoptotic
pathway, and stabilizes microtubules [49, 50].
Suberoylanilide bis hydroxamine (SAHA, Vorinostat).
Vorinostat is a HDACI that reacts with and blocks the cata-
lytic site of HDACs [51, 52]. SAHA induces the activation of
caspase-8 and caspase-9, results in the upregulation of glyco-
delin and acetylated H3 and H4 bound to either Tig1 or
C/ebpa gene, downregulates the expression of Bcl-2, cyclin
D1, and D2, increases the levels of FOXA1, E-cadherin,
p21, and p27, causes a dramatic decrease of FLIP mRNA
and protein levels, and induces apoptosis in EC [30, 40, 41,
53–56]. Sarfstein et al. examined SAHA’s mechanism of
action in type I and type II EC cell lines in the presence or
absence of IGF-I and found out that Vorinostat exhibits a
potent apoptotic and antiproliferative effect in both type I
and II EC cells through interaction with the insulin-like
growth factor signaling pathway [57]. SAHA is also effective
at reducing AURKA expression in EC, a cell-cycle-regulated
kinase that functions in spindle formation and chromosome
segregation during the M phase of the cell cycle [58].
Panobinostat (LBH589). LBH589 is a potent pan-
deacetylase inhibitor [59]. Treatment with LBH589 induces
a profound upregulation of PR mRNA and MIG6, cell cycle
arrest in G1, and a downregulation of the oncogene MYC
[32, 60, 61]. Knockdown of metadherin sensitizes EC cells
to cell death induction by death receptor ligand TRAIL
and LBH589 co-treatment [62] while the combination of
proteasome and LBH589 overcomes the impact of gain-of-
function p53 mutations [63].
Sodium butyrate (NaB). NaB is a part of the metabolic
fatty acid fuel cycle that also acts as a HDACI [64]. NaB induces
upregulation of p21, p27, acetyl H3, and H4 and inhibition of
transcription from multiple ERαpromoters, cell cycle arrest,
and apoptosis [41, 42, 65]. The addition of NaB significantly
enhances adriamycin cytotoxicity for the primary EC cells with
high human telomerase reverse transcriptase expression [66].
NaB has been also reported to inhibit the self-renewal capacity
of endometrial tumor side-population cells by promoting the
production of intracellular ROS and by upregulating the
expression of the phospho-p38 mitogen-activated protein
kinase, γH2AX, acetyl H3, p21, and p27 [67, 68].
Valproic acid (VPA). VPA is a HDACI approved for the
treatment of epilepsy [24, 69]. VPA inhibits proliferation,
induces cell cycle arrest, enhances the apoptotic index in EC
cell lines, upregulates E-cadherin mRNA and protein levels,
and downregulates Bcl-2 mRNA levels [56]. Moreover, VPA
enhances the action of antiestrogens in ERα-positive breast
cancer cells and blocks tamoxifen-induced proliferation of
uterine cells [70]. Cotreatment with VPA and the Aurora
CH3
CH3
O
N
O
NH
O
HN
ONH
N
O
CH3
O
CH3
Apicidin
CH3CH3
O
NH
OH
O
N
CH3
CH3
Trichostatin A (TSA)
NH
O
O
NH OH
Suberoylanilide bishydroxamine (SAHA)
CH3
NH
NH
O
NH
HO
Panobinostat (LBH589)
Na+(I)
CH3O
Sodium Butyrate (NaB)
CH3
CH3
O
O–
O–
Valproic acid (VPA)
CH3O
HN S
S
ONH
O
O
NH
O
CH3
CH3
HO
OBP-801/YM753
SO
O
NH
O
NH OH
ONO
O
HN
OH
Scriptaid
CH3
O
NH
O
O
O
NH
O
NH
S
S
ONH
CH3
CH3
CH3
CH3
Romidepsin (FK228)
N
OH
O
NH
S
S
NH
O
N
OH
OH
Br
Br OH
Psammaplin A (PsA)
NH
NH
S
O
O
OH
MHY2256
Figure 2: Chemical structures of HDACIs used in EC treatment
studies.
5Disease Markers

kinase inhibitor VE465 induces enhanced apoptosis, cleaved
PARP, and cytotoxic effects in EC cells [71].
OBP-801/YM753. Combination of the novel HDAC inhib-
itor OBP-801/YM753 and the PI3K inhibitor LY294002
synergistically induces apoptosis in human EC cells due to
increase of BIM with accumulation of ROS [72].
Oxamflatin. Oxamflatinis is a HDACI that induces tran-
scriptional activation of jun D and morphological reversion
in v-Kras-transformed NIH3T3 cells [73]. Administration
of Oxamflatin causes morphologic changes, loss of mito-
chondrial membrane potentials, and cleavage of PARP,
caspase-8, and caspase-9, confirming the activation of apo-
ptotic cascades in EC cells [15].
Scriptaid. Scriptaid is a potent HDACI with a >100-fold
increase in histone acetylation, with relatively low toxicity
[74]. Exposure to Scriptaid decreases the proportion of cells
in the S phase, increases the proportion in the G0/G1 and/or
G2/M phases of the cell cycle, upregulates the expression of
E-cadherin, acetyl-H3 and acetyl-H4, p21, and p27, downre-
gulates the expression of cyclin A and Bcl-2, and induces
apoptosis in EC cells [75].
Romidepsin (FK228). FK228 is a HDACI which has been
confirmed as a useful anticancer agent [76]. In EC cell lines,
FK228 induces apoptosis and cell cycle arrest at G0/G1
phase, increases the mRNA and protein expressions of p53,
p21, cleaved caspases such as 3, 7, and 8, and PARP, and
upregulates the acetylation of H3 and H4 [77].
Psammaplin A (PsA). PsA is a natural bromotyrosine
derivative from a two-sponge association, Poecillastra sp.
and Jaspis sp., which was first isolated from the Psammaply-
silla sponge. PsA induces the expression of acetylated H3
and H4 histone proteins, upregulates the expression of
cyclin-dependent kinase inhibitors and p21, and downregu-
lates the expression of p53, pRb, cyclins, and CDKs, which
lead to induce cell cycle arrest [78].
MHY2256. MHY2256 is a novel HDACI that inhibits
class III HDAC sirtuin (SIRT). MHY2256 reduces both
SIRT1 enzyme activity and SIRT protein levels in EC cells,
inhibits cell cycle distribution, increases p53 levels, reduces
the expression of mouse double minute 2 (MDM2), and
induces apoptotic/autophagic cell death [79].
Takai et al. have summarized the half maximal inhibi-
tory concentrations (IC50) of the different classes of HDA-
CIs which indicate how much of each HDACI is needed to
inhibit in vitro cell growth in EC cell lines by 50% [14].
1.3. In Vivo Impact of HDACI Use in EC. Several studies
have examined the anti-tumor effect of HDACIs on human
EC cells in mouse models (Table 3).
Apicidin downregulates HDAC3 and HDAC4 and sup-
presses the tumor growth of transplanted Ishikawa cells,
the expression of proliferative cell nuclear antigen (PCNA),
and vascular endothelial growth factor (VEGF) in tumor
xenograft model, respectively [37].
Co-treatment with TSA and paclitaxel results in a signifi-
cant reduction in tumor weight, increases microtubule stabili-
zation, and induces apoptosis as well as tubulin acetylation in
mouse xenograft models [50].
Combination of Vorinostat and caspase-8 inhibition causes
a nearly complete inhibition of tumor xenograft growth [53].
NaB results in marked suppression of tumor growth and
SA-β-gal activity in tumor xenograft models [65].
VPA and MHY2256 significantly inhibit human uterine
tumor growth without toxic side effects in mouse models
[41, 79]. Notably, VPA inhibits tumor growth, upregulates
CDH1 mRNA, and downregulates Bcl-2 mRNA levels
in vivo [56]. Yoshioka et al. showed that combined treatment
with OBP-801/YM753 and LY294002 significantly suppressed
tumor growth compared to the control in vivo [72].
In a surgical window trial of women with newly diag-
nosed endometrioid EC, co-treatment with medroxyproges-
terone acetate and the HDACI Entinostat resulted in the
reduction of PR H-scores and Ki-67 levels [80].
2. Conclusions
The present review summarizes the important role of
HDACs in EC development and progression and highlights
the potent antitumor effects of various HDACIs on EC cell
lines both in vitro and in vivo. HDACs seem to be involved
in the tumorigenesis of both EC tumor types and account for
high-grade, aggressive carcinomas with worse prognosis and
Table 3: Antitumor effects of HDACIs on human EC cells in mouse models.
HDACI Upregulatory
effects
Downregulatory
effects Synergetic effects References
Apicidin n/a
HDAC3, HDAC4,
PCNA, VEGF,
Tumor growth
n/a [37]
TSA n/a n/a Paclitaxel: reduction in tumor weight, increase in microtubule
stabilization, apoptosis induction, tubulin acetylation induction [50]
SAHA n/a n/a Caspase-8 inhibition: tumor growth inhibition [53]
NaB n/a SA-β-gal activity,
Tumor growth n/a [65]
VPA CDH1
mRNA
Bcl-2,
Tumor growth n/a [41, 56, 79]
MHY2256 n/a Tumor growth n/a [41, 79]
OBP-801/YM753 n/a n/a LY294002: tumor growth inhibition [72]
6 Disease Markers

decreased overall survival. HDACIs represent promising
therapeutic agents that inhibit tumor growth, enhance the
transcription of silenced physiologic genes, and induce cell
cycle arrest and apoptosis in EC cells. Notably, the combina-
tion of HDACIs with traditional chemotherapeutic agents
shows synergistic cytotoxic effects in EC cells. Nevertheless,
clinical trials are needed to verify the clinical utility and
safety of HDACIs in the treatment of women with EC, to
investigate possible adverse side effects following their
administration to patients and to assure their effectiveness
depending on HDAC expression by EC cells.
Conflicts of Interest
The authors declare no conflict of interest.
Authors’Contributions
Literature analysis and conceptualization were contributed
by I.P., A.P., C.G., and S.T.; original draft preparation and
writing were performed by I.P.; art work was done by A.P.;
review and supervision were contributed by S.T. and C.G.
All authors have read and agreed to the submitted version
of the manuscript.
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