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The roles of histone demethylase UTX and JMJD3 (KDM6B) in cancers: Current progress and future perspectives



Aberrant epigenetic reprogramming occurs frequently in the development of tumors. Histone H3 lysine 27 trimethylation (H3K27me3) exerts a repressive epigenetic mark on a large number of genes. UTX and JMJD3 are the only two histone demethylases which activate gene expression via demethylating H3K27me3 to H3K27me2 or H3K27me1. Current studies show that dysregulation of these two proteins are heavily linked to oncogenesis in various tissue types. Accumulating evidence suggested that there is remarkable therapeutic potential of targeting JMJD3 or UTX in different types of cancer. Herein, we shall give a brief review on the functional roles of JMJD3 and UTX in cancers and evaluate the available compounds and agents targeting UTX and JMJD3. Finally, we also discuss the several modalities that target UTX and JMJD3 for cancer therapy. This review will help to develop novel strategies to abolish or restore effects of UTX and JMJD3 in the pathogenesis of cancer.
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The Roles of Histone Demethylase UTX and JMJD3 (KDM6B) in
Cancers: Current Progress and Future Perspectives
Zhan Gang Xiao1,*, Jing Shen1, Lin Zhang2, Long Fei Li1, Ming Xing Li1, Wei Hu1,
Zhi Jie Li1 and Chi Hin Cho1,2,*
1Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest
Medical University, Luzhou, 646000, Sichuan, PR China; 2School of Biomedical Sciences, Faculty of Medi-
cine, the Chinese University of Hong Kong, Hong Kong, China
Received: May 26, 2016
Revised: July 07, 2016
Accepted: July 15, 2016
DOI: ????????????
Abstract: Aberrant epigenetic reprogramming occurs frequently in the de-
velopment of tumors. Histone H3 lysine 27 trimethylation (H3K27me3) ex-
erts a repressive epigenetic mark on a large number of genes. UTX and
JMJD3 are the only two histone demethylases which activate gene expres-
sion via demethylating H3K27me3 to H3K27me2 or H3K27me1. Current
studies show that dysregulation of these two proteins are heavily linked to
oncogenesis in various tissue types. Accumulating evidence suggested that
there is remarkable therapeutic potential of targeting JMJD3 or UTX in dif-
ferent types of cancer. Herein, we shall give a brief review on the functional
roles of JMJD3 and UTX in cancers and evaluate the available compounds
and agents targeting UTX and JMJD3. Finally, we also discuss the several modalities that
target UTX and JMJD3 for cancer therapy. This review will help to d evelop novel strategies
to abolish or restore effects of UTX and JMJD3 in the pathogenesis of cancer.
Keywords: UTX, JMJD3, H3K27, cancer, therapeutic target.
Polycomb-group proteins are a family of proteins
that were first discovered in fruit flies, which can epi-
genetically silence their target genes by chromatin-
remodeling [1]. A large number of genes can be si-
lenced by polycomb proteins through specific lysine 27
on histone H3 (H3K27) [2]. The repressive modifica-
tion of histone tail H3K27 trimethylation (H3K27m3),
is catalysed by the polycomb repressive com-
plexPRC including PRC1 and PRC2. PRC1
mainly contains CBXs, PHC1/2/3, RING1a/b and
BMI1 [3] while PRC2 consists of the enhancer of zeste
homolog 2 (EZH2), suppressor of zeste 12 (Suz12),
*Addresses correspondence to these authors at the Rm 521A,
School of Biomedical Sciences, Faculty of Medicine, The Chinese
University of Hong Kong, Shatin, N.T., Hong Kong, China; Tel:
(852) 3943 6886; Fax: (852) 2603 5139; Email:; and Laboratory of Molecular Pharmacology,
Department of Pharmacology, School of Pharmacy, Southwest
Medical University, Luzhou, 646000, Sichuan, P.R. China;
and extra sex combs (Esc) [4]. Briefly, PRC2 first
binds to chromatin and trimethylates H3K27. The
methylated molecule H3K27me3 is then recognized by
PRC1 and finally leads to chromatin compaction and
pausing of RNA polymerase II [5].
H3K27me3 is frequently associated with gene re-
pression, and it is a critical epigenetic event occurred
during tissue development, stem cell fate determination
and the processes of cancer occurrence/progression [6].
To our knowledge, The Jumonji domain containing-3
(JMJD3), also known as lysine (K)-specific demethy-
lase 6B (KDM6B) and the ubiquitously transcribed X-
chromosome tetratricopeptide repeat protein (UTX) are
the only two proteins [7] that can demethylate
H3K27me3 to H3K27me2 or H3K27me1, and dissoci-
ate polycomb group complexes [8, 9]. Accumulating
evidence showed that alteration of the enzyme activity
controlling H3K27 methylation contributed to carcino-
genesis. Polycomb-group proteins exhibit oncogenic
phenotypes by repressing tumor suppressor genes in a
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2 Current Medicinal Chemistry, 2016, Vol. 23, No. ?? Xiao et al.
variety of cancers, such as lymphoma [10, 11], bladder
cancer [12], pancreatic ductal adenocarcinoma (PDAC)
[13], breast cancer [14], prostate cancer [15] and colon
cancer [16]. JMJD3 and UTX reverse polycomb group-
mediated transcriptional repression by demethylating
H3K27me3, which is also reported to play vital roles in
different cancers [17, 18]. It has been shown that UTX
and JMJD3 play various biological roles in diverse
pathological processes of multiple malignancies. This
review will focus on the role of UTX and JMJD3 in
cancers, and comprehensively discuss the current un-
derstandings of the structure and biological activities of
UTX and JMJD3, and provide the basis to inspire the
development of novel strategies to target UTX and
JMJD3-related actions in the pathogenesis of cancers.
UTX protein is encoded by the X chromosome, con-
tains six TPR (tetratricopeptide repeat) domains and
the JmjC domain [19]. The UTY protein is the Y-
linked homolog of UTX and shares high degree ho-
mology with UTX. The human UTY gene resides on
the Y chromosome and is expressed in most tissues in
the male [19]. Although the previous studies showed
that UTY was inactive as a JmjC lysine demethylases,
Walport et al demonstrated a lower level of activity of
UTY with respect to H3K27Me3 substrates when com-
pared with JMJD3/UTX in vitro [20]. The complete
picture of UTY catalyzed demethylation should be fur-
ther elucidated. The UTX gene escapes X inactivation
in females and is ubiquitously expressed [21]. UTX
protein is located in the nucleus and catalyzes the de-
methylation of H3K27m3 [18]. Structural studies on
UTX showed that substrate specificity is mediated both
by the JmjC domain and a novel zinc-binding domain
located downstream of the JmjC domain [22]. There-
fore, this protein catalyzes the removal of methyl group
from H3K27m3 by recognizing methylated H3K27 or
the residues 17-21 of H3. Beside JmjC domain and
zinc-binding domain which are indeed important for
demethylation, some other domains contained in UTX
exhibit no demethylation activity [22]. Therefore, the
functional elucidations of these domains are necessary
to be studied in the future.
Human JMJD3 gene is located on chromosome 17,
and contains 22 exons which encode 1682 amino acid
residues. In the absence of TPR domains, JMJD3 can
act as a specific demethylase for H3K27me3 via its
JmjC catalytic domain [23]. The N-terminal region of
the JMJD3 is responsible for its nuclear localization,
which is required for effective demethylation of
H3K27me3. Whereas, the C-terminal region harboring
the catalytic JmjC domain cannot situate into the nu-
cleus [24]. It was confirmed that the subcellular local-
ization of JMJD3 was dynamically regulated to modu-
late H3K27me3 status [24]. On the other hand, the
functional nuclear localization signals (NLSs) in its N-
terminal region of JMJD3 mediate the nuclear localiza-
tion of this protein. The current evidence proved that
nuclear accumulation of JMJD3 was indispensable for
effective demethylation of H3K27me3 [24]. This study
also indicates that some other biological functions of
JMJD3 should be further explored.
3.1 UTX in Cancers
UTX was identified as a histone demethylase which
specifically demethylates H3K27me3 and it has been
proven to be essential during cellular reprogramming
[25], embryonic stem cell (ESC) and embryonic devel-
opment [26-29], tissue-specific differentiation includ-
ing cardiac development and hematopoiesis [29, 30].
Recently, UTX was proven to play a crucial role in the
resolution and activation of numerous retinoic acid
(RA)-inducible bivalent genes during the RA-driven
differentiation of mouse ESCs [31]. It has also been
reported that constitutional UTX defects also cause the
Kabuki syndrome which may develop different types
of cancer including pre-B-ALL [32], hepatoblastoma
[33], neuroblastoma [33, 34], Burkitt lymphoma [35],
and fibromyxoid sarcoma [36], indicating that the Ka-
buki syndrome is a cancer predisposition syndrome. An
essential role for UTX in resolution and activation of
bivalent promoters
During the years, inactivated somatic mutations and
deletions of UTX were frequently identified in cancers
[37, 38]. The truncating mutations in the region coding
for the JmjC domain of UTX was confirmed as the
main cause of bladder cancer [39]. The complete loss
of UTX is also required for malignant transformation in
medulloblastoma patients [40, 41]. Zha et al. reported
that the epigenetic regulation of E-cadherin by UTX
inhibited migration and invasion of colon cancer cells
[42]. UTX was also reported to transcriptionally acti-
vate tumor suppressor Rb pathway genes by reducing
cell proliferation to suppress cell growth [43], and
played a key role in regulating DNA repair in response
to DNA damage in Drosophila melanogaster [44]. All
these studies indicate a tumor suppressive role of UTX
in cancers. Most recently, UTX was identified as a pro-
oncogenic cofactor essential for leukemia maintenance
The Roles of Histone Demethylase UTX and JMJD3 Current Medicinal Chemistry, 2016, Vol. 23, No. ?? 3
in TAL1-positive (but not TAL1-negative) T-cell acute
lymphoblastic leukemia [45]. However, it was previ-
ously described as a tumor suppressor in this cancer,
now has a dichotomy function in cancer. UTX is also
reported to contribute to cellular proliferation by acti-
vating oncogenic gene in breast cancer [46], indicating
a complicated role of UTX in the pathogenesis of can-
Currently, the functional consequences of cancer re-
lated UTX mutations are still poorly studied. It has
been shown that UTX protein expression was silenced
in UTX mutant cancer cell lines [37]. Ectopic expres-
sion of mutant UTX in cancer cells could increase cell
growth and decrease in H3K27me3 levels [47]. Mean-
while, re-expression of wild type UTX also strongly
increased the growth of cancer cells and increased in
H3K27me3 levels [45]. Furthermore, over-expression
of wild type UTX in UTX mutant cancer cell lines
could suppress the expression of Polycomb target
genes by reducing H3K27me3 levels at the promoters
of these targets and concomitantly inhibition of cell
proliferation [37]. Finally, the mutagenesis screening in
a pancreatic cancer mouse model found more than 10%
of mutated genes involved in chromatin regulation in-
cluding UTX. This un-biased screening result also con-
firmed the tumor suppressive role of UTX in pancreatic
cancer [48]. Collectively, the above studies show that
UTX mutation is a major cause of different cancers and
recovery of this protein maybe a promise strategy for
cancer therapy. Meanwhile, due to the opposite func-
tions of UTX in some cancer subtypes, personalized
therapies may be required to efficiently treat different
subtypes of cancer like T-cell acute lymphoblastic leu-
kemia through targeting UTX.
3.2. JMJD3 in Cancers
Up to now, the role of JMJD3 in cancers is highly
controversial. The tumor suppressive role of JMJD3
was identified in colorectal, lung, liver, hematopoietic
malignancies [49, 50], and also glioma [51], non-small
lung cell carcinoma (NSCLC) [52], pancreatic ductal
adenocarcinoma [53] and B-cell lymphoma [54].
JMJD3 functions in tumor suppression as a regulator
involved in different signal pathways. Agger et al., re-
ported that JMJD3 was recruited to the INK4A-ARF
locus which encoded the tumor suppressor proteins
p16INK4A and p14ARF, and activated p16INK4A ex-
pression in human diploid fibroblasts [49]. Barradas et
al. reported that JMJD3 activated p16/INK4a, and
caused p16/INK4a-dependent cell cycle arrest in mouse
embryo fibroblasts [9]. Another study found that
JMJD3 acted as a tumor suppressor by regulating p53
protein nuclear stabilization in glioblastoma stem cells
[51]. Recently, JMJD3 was also reported to be a tumor
suppressor by inducing the expression of the growth-
suppressive miR-99a/let7c/125b-2 cluster in prostate
cancer and mediating p15/INK4B expression in colon
cancer [55, 56]. In B-cell lymphoma, JMJD3 promotes
survival of diffuse large B-cell lymphoma subtypes via
interacting with IRF4 [54].
Conversely, the carcinogenic role of JMJD3 was
also reported in other types of cancer including gliomas
[57], kidney cancer [58], breast cancer [59], prostate
cancer [60], melanoma [61], renal cell carcinoma [62],
Hodgkin's lymphoma [63] and myelodysplastic syn-
drome [64]. Elevated levels of JMJD3 are usually
found in these tumor types. JMJD3 was reported to
transcriptionally activate RUNX2 expression and asso-
ciated with RUNX2 to promote proliferation of chon-
drocytes [65], and JMJD3 also activated the anti-
apoptotic gene, BCL2, in hormone-dependent breast
cancer cells [66]. However, current investigations
could not provide sufficient information on the mecha-
nism of action to elucidate the oncogenic role of
JMJD3 in cancers. It only reported that TGF-β could
induce JMJD3 expression in normal mammary epithe-
lial cells and JMJD3 was involved in EMT to exert its
oncogenic effect in clear cell renal cell carcinoma [67].
Therefore, the mechanistic study of the oncogenic role
of JMJD3 in cancer is urgently needed.
On the other hand, JMJD3 was also proved to play a
vital role in inflammation. JMJD3 can be induced by
bacterial products and inflammatory cytokines in
macrophages [23], [68]. Most of lipopolysaccharide
(LPS)-activated inflammation related genes are JMJD3
targets [69], which were not associated with detectable
levels of H3K27me3. These studies indicate that
JMJD3 may involve in inflammation in a demethyla-
tion-independent manner. Interestingly, our preliminary
finding showed that JMJD3 suppressed tumor growth
by ectopic expression of mutant JMJD3 (lacking de-
methylation activities) in cancer cells. Since inflamma-
tory responses play a decisive role at different stages of
tumor development [70], JMJD3 may build a bridge
between inflammation and cancer with un-
characterized functions in addition to its known de-
methylation activity.
The H3K27m3 demethylases provide potentially
new opportunities for therapeutic intervention in a wide
range of therapeutic areas including inflammation and
oncology. Based on the demethylase enzyme activities
4 Current Medicinal Chemistry, 2016, Vol. 23, No. ?? Xiao et al.
of JMJD3, Mulji et al., used a high-content imaging
approach that had been used to prosecute a medium-
throughput screen (87500 compounds) and successfully
identified the first JMJD3 inhibitor [71]. Thereafter,
using structure-guided small-molecule and chemopro-
teomics approach, Kruidenier et al., found two inhibi-
tors termed GSK-J1/4 which could inhibit the expres-
sion of both UTX and JMJD3 [72, 73]. They also dem-
onstrated that GSK-J1/4 could reduce LPS-induced
pro-inflammatory cytokine production by human
macrophages, a process that depends on both JMJD3
and UTX. This study paves the road for designing
small-molecule modulators to allow selective pharma-
cological intervention across UTX and JMJD3.
The inhibitors of H3K27m3 demethylases were also
reported to selectively inhibit cancer growth. A com-
pound named JIB-04 could reduce breast tumor burden
and prolong survival in in vivo mouse model through
modulating JmjC histone demethylase activity includ-
ing JMJD3 [74]. GSK-J1 and its isomers are one class
of the most encouraging potential lead compounds that
act as inhibitors of the JMJD3 subfamily. It was re-
ported that inhibition of GSK-J1 on UTX could de-
crease the expressions of UTX downstream targets and
finally suppress osteoblast differentiation [75]. Re-
cently, Benyoucef et al. provided a novel therapeutic
approach based on UTX inhibition through in vivo ad-
ministration of GSK-J1 that efficiently killed TAL1-
positive primary human leukemia [45]. Sakaki et al.
found that H3K27 methylation exhibited an inhibitory
role in the maintenance of ovarian cancer stem cells
(CSCs) and that one of GSK-J1 isomers, GSK-J4 may
represent a novel class of CSC-targeting agents [76].
Meanwhile, GSK-J4 also acts as a promising agent for
cancer therapy in other cancer types such as acute lym-
phoblastic leukaemia [77], pediatric brainstem glioma
[78] and diffuse intrinsic pontine glioma [79].
Due to the limited information on the structure-
activity relationship of GSK-J1 and its isomers, Hu et
al., initialized a medicinal chemistry modification
based on GSK-J1 structure, and they finally identified
several compounds which exhibited similar activities as
with GSK-J1. The inhibition of these compounds on
LPS-stimulated genes was also proven in macrophages
[80]. Some other inhibitors of JmjC demethylases have
been identified including the α-ketoglutaric acid mim-
ics N-oxalylglycine [81], methylstat [82], and catechols
[83]. However, all these inhibitors can selectively in-
hibit some or all histone demethylases activities with-
out specificity to anyone of the histone demethylase
member. The inhibitors that could be able to specifi-
cally target UTX or JMJD3, need further exploration.
More importantly, the tumor suppressive role of UTX
and JMJD3 in different cancer types is well character-
ized, which allows researchers to pursue novel UTX
and JMJD3 activators for cancer therapy.
It is well known that H3K27me3 is associated with
the repression of gene expression. EZH2 is the core
catalytic unit of PRC2 complex which controls de-
methylation and trimethylation of H3K27
(H3K27me2/3) [84]. EZH2 is firstly considered onco-
genic in solid tumors and later proven to be tumor sup-
pressive in myeloid cancers [85]. Up to now, UTX and
JMJD3 are the only two demethylases identified for
histone H3K27, which show both oncogenic and tumor
suppressive characteristics in different types of cancer
as we have reviewed. Undoubtedly, the roles of UTX
and JMJD3 in cancer are strengthened with the fact that
EZH2 is typically considered as a tumor suppressor as
well as oncogene. Therefore, agents that activate or
inhibit the effect of EZH2 in cancers may be also ap-
plied to treat the types of cancer in which UTX or
JMJD3 is deregulated. What is more important is to
study the pivotal roles of UTX and JMJD3 in cancer
development, and they may be the therapeutic targets
for different types of cancer. In the following sections
we shall discuss additional features of UTX and JMJD3
which may shed light on the development of novel ap-
proaches for cancer therapy.
5.1. Therapeutic Strategies by Targeting UTX
Downregulation or silence of UTX frequently hap-
pened in most reported cancers. The currently identi-
fied inhibitors of UTX are far more enough to build
efficient therapeutic strategies for cancers. In malignant
cells, low expression of UTX could be resulted from
both genetic and epigenetic events. Therapeutic strate-
gies to activate UTX system at the transcriptional,
translational or protein levels could be promising ap-
proach for the cancer types, in which UTX expression
is low or silenced. It was reported that the dissociation
of histone deacetylase 1 (HDAC1) from promoters of
targeted genes could recruit UTX to its targeted gene
promoters, leading to decreased H3K27 trimethylation
[86]. This study illustrates the possibility that we could
explore agents that target the upstream signaling path-
ways which could activate the expression of UTX. Up
to now, we have not found any studies so far that report
the activators of UTX. This may attribute to the fact
that most molecular targeted therapies are inhibitors of
The Roles of Histone Demethylase UTX and JMJD3 Current Medicinal Chemistry, 2016, Vol. 23, No. ?? 5
oncogenes. Indeed agents to act on the inactivated tu-
mor suppressor genes seem to be harder for drugs to
have such ability. However in carcinogenesis, altera-
tions of tumor suppressor genes are far more frequent
than that of oncogenes across multiple types of human
cancer [87]. The promising strategies directed at UTX,
or acted on pathways controlled by UTX, should
emerge in future studies.
Many gene mutations possess gain-of-function ef-
fects. Take p53 as an example, the mutation in cancer
cells lowered the melting temperature and stability of
p53 in its DNA binding domain, causing the denatura-
tion of p53 [88], and an in silico screened compound
targeted rescue of a destabilized mutant of p53 [89].
One of our studies also revealed that a library screened
compound can restore the tumor suppressive effect of
mutant p53 in liver cancer [90]. Similar to p53, previ-
ous studies demonstrated that UTX mutation was a ma-
jor cause of different cancers [37]. Although no modu-
lators of UTX mutant are reported from the current
studies, discovery of some compounds that restore or
enhance a particular molecular function of mutant UTX
may provide us a selective way to restore the tumor
suppressive role of UTX.
UTX also acts as an oncogene in TAL1-positive T-
cell acute lymphoblastic leukemia [45]. Besides screen-
ing the inhibitors of UTX for cancer therapy, depletion
of UTX protein in cancer cells is the most direct way to
attenuate its effect. Current studies proved that degra-
dation of UTX transcript via small-interfering RNA
(siRNA) duplexes suppressed the oncogenic role of
UTX in TAL1-positive T-cell acute lymphoblastic leu-
kemia [45], which provide a basis for an RNAi-
mediated therapy. More interestingly, the online data-
base-Connective Map, which uses gene-expression sig-
natures to connect small molecules, genes, and disease
[91], provides us a novel way to find the potential
modulators of UTX for cancer therapy. The gene-
expression profiles after gain or loss of UTX in cancer
cells could be used to compare with the gene-
expression profiles obtained from cells after the treat-
ment with different compounds. The hit compounds
may be the inhibitors or activators of UTX based on
calculating the sum of positive and negative matches in
the individual gene expression profile [92].
5.2. Therapeutic Strategies by Targeting JMJD3
Like UTX, JMJD3 also acts as tumor suppressor or
oncogene in different types of cancer. Mutations and
deletions may contribute to the downregulation of
JMJD3 expression in cancers. Ene et al. proved that
missense mutations and promoter methylation of the
JMJD3 gene occurred in gliomas [51]. And Pereira et
al. found that vitamin D can induce the tumor suppres-
sive activity of JMJD3 in colon cancer [50]. These
studies demonstrated a promising way to restore the
tumor suppressive function of JMJD3 by compounds
for cancer therapy. Guo et al. identified a nickel com-
pound that could activate the oncogenic role of JMJD3
in kidney cancer cells [58], this study provides us a
potential JMJD3 modulator that may be applied to acti-
vate tumor suppressive action of JMJD3 on other ma-
lignances. Meanwhile, using library screening or con-
nectivity map searching to identify the activators of
JMJD3 is also an option for cancer therapy by targeting
its tumor suppressive characteristic.
Conversely, evidences showed that JMJD3 exhib-
ited oncogenic role in several cancers. In addition to
some inhibitors of JMJD3 as we reviewed, using
siRNA or shRNA to degrade JMJD3 is also promising
in cancer suppression. It is reported that knockdown of
JMJD3 by siRNA or shRNA significantly inhibited
breast cancer cell invasion [59]. Restoring normal regu-
lation on JMJD3 is another feasible approach to reverse
the epigenetic effects of ectopic JMJD3. As mentioned,
defect in microRNAs-mediated post-transcriptional
regulation on JMJD3 is one of the reasons leading to
JMJD3 overexpression. Study showed that miR-146A
was downregulated in the osteogenic differentiation of
human mesenchymal stem cells (hMSCs), and ectopic
expression of this microRNA significantly inhibited
JMJD3 expression and osteogenic differentiation in
hMSCs [93]. The microRNA approach allows us to
develop another therapeutic strategy based on the ac-
tions of microRNA in the environment of cancer. Cur-
rently, the mechanisms that lead to upregulation of
JMJD3 expression in cancer is still unknown, however,
some mutations/deletions in significant genes may
manifest as aberrant JMJD3 activity in cancer. EZH2 is
reported to be mutated/deleted in myeloid malignancies
[94], which may mimic aberrant JMJD3 activity result-
ing in loss of polycomb-mediated silencing at target
cancer genes. Therefore, some activators of EZH2 may
be used to silence the oncogenic activities of JMJD3. It
includes some transcriptional activators of EZH2, such
as members of E2F family and C-MYC activators [95]
and also some microRNAs or long non-coding RNAs
(lncRNAs) that post-transcriptionally regulate EZH2
expressions [96].
Current studies show that the roles of both UTX and
JMJD3 are converse in different types of cancer, thus
6 Current Medicinal Chemistry, 2016, Vol. 23, No. ?? Xiao et al.
helping us to develop personalized medicines for dif-
ferent cancers by targeting on these two proteins.
Moreover, the functions of UTX and JMJD3 are also
converse even in the same cancer types. It is reported
that JMJD3 was essential for the initiation and mainte-
nance of T-ALL while UTX functioned as a tumor
suppressor and was frequently genetically inactivated
in this cancer [77]. Therefore, the most recently identi-
fied modulators that target on histone demethylase
show obvious limitation in the therapeutic potential of
this type of cancer. Some other strategies like develop-
ing the specific modulators of UTX and JMJD3 target-
ing the specific domains of UTX or JMJD3 should be
encouraged and explored.
On the other hand, the demethylating effect of UTX
can be elucidated with a good knowledge in the crystal
structure of JMJD3 [22]. Therefore a well defined
structure of JMJD3 is of urgency to be solved in future.
It has been proven that JMJD3 was involved in in-
flammation in a demethylation-independent manner.
Previous study demonstrated that JMJD3 played a role
in general chromatin remodeling that is independent of
its H3K27 demethylase potential [97, 98]. Therefore,
JMJD3 may also function in cancer development with
activities other than its histone demethylation activity.
Similar to UTX, further studies are needed to clarify
other functional domains beside the one on JmjC dur-
ing cancer development.
H3K27m3 = histone tail H3K27 trimethylation
PRC = polycomb repressive complex
EZH2 = enhancer of zeste homolog 2
Suz12 = suppressor of zeste 12
Esc = extra sex combs
JMJD3 = The Jumonji domain containing-3
(KDM6B) = lysine (K)-specific demethylase 6B
UTX = ubiquitously transcribed X-
chromosome tetratricopeptide repeat
NSCLC = non-small lung cell carcinoma
HDAC1 = histone deacetylase 1
siRNA = small-interfering RNA
hMSCs = human mesenchymal stem cells
lncRNAs = long non coding RNAs
NLS = nuclear localization signal
RA = retinoic acid
ESC = embryonic stem cell.
The author(s) confirm that this article content has no
conflict of interest.
Supported by Grants from the National Natural Sci-
ence Foundation of China (Grant No. 81503093 and
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... UTX1 (KDM6A) and JMJD3 are the KDM6 family members that demethylate H3K27me3 [39,40]. JMJD3 contains a Jumonji C (JmjC) domain (demethylates histones) and a C-terminal segment that is embedded with a GATA-like (GATAL) domain [41,42]. The KDM6A protein has a catalytic JmjC domain at the C terminus and six tetratricopeptide repeat (TPR) domains at the N terminus [43] (Fig. 1). ...
Full-text available
The Jumonji domain-containing protein-3 (JMJD3) is a histone demethylase that regulates the trimethylation of histone H3 on lysine 27 (H3K27me3). H3K27me3 is an important epigenetic event associated with transcriptional silencing. JMJD3 has been studied extensively in immune diseases, cancer, and tumor development. There is a comprehensive epigenetic transformation during the transition of embryonic stem cells (ESCs) into specialized cells or the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Recent studies have illustrated that JMJD3 plays a major role in cell fate determination of pluripotent and multipotent stem cells (MSCs). JMJD3 has been found to enhance self-renewal ability and reduce the differentiation capacity of ESCs and MSCs. In this review, we will focus on the recent advances of JMJD3 function in stem cell fate.
... The repressive modi cation of histone tail histone H3 lysine 27 (H3K27) trimethylation is catalysed by the polycomb group protein EZH2 [5]. JMJD3 and UTX are the only two proteins [6]that demethylate H3K27me3 to H3K27me2 or H3K27me1, and dissociate polycomb group complexes [7,8]. Evidences showed that alteration of the enzymes activity controlling H3K27 methylation contributed to carcinogenesis. ...
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Background: JMJD3 is a jmjd domain containing histone demethylase which can remove methyl groups from lysine 27 of histone 3 (H3K27) to active histone methylated genes. Previous studies have demonstrated that JMJD3 played a crucial role in inflammation. Methods: Our study showed that JMJD3 was significantly down-regulated in pancreatic ductal adenocarcinoma (PDAC) cell lines and tissues. Restored expression of JMJD3 inhibited oncogenic phenotypes of PDAC cells, including cell proliferation, cell migration, and in vivo tumorigenicity, indicating a tumor suppressive role. Gene-expression microarray revealed that Hexokinase domain containing 1 (HKDC1) was one of the JMJD3 downstream targets. Results: The expression of JMJD3 and HKDC1 in PDAC tissues was positively correlated. High H3K27 tri-methylation (H3K27me3) status in HKDC1 gene was attenuated by ectopic expression of JMJD3 in PDAC cells, suggested that JMJD3 regulated HKDC1 expression by histone demethylation activity. The tumor suppressive role of HKDC1 in PDAC was also proved. Moreover, HKDC1 was demonstrated to competitively bind to spectrin beta Ⅱ to induce cytoskeleton disruption, which may contribute to tumor suppression. Conclusion: Taken together, our study indicates that JMJD3 may disrupt spectrin-dependent cytoskeleton via activation of HKDC1 to suppress PDAC.
... Gene expression is epigenetically regulated through epigenetic modification. The Jumonji domain containing-3 (JMJD3, KDM6B) has been identified as H3K27 demethylase that catalyzes the demethylation of H3K27me2/3 and is associated with the repression of gene expression [11]. Current studies show that dysregulation of JMJD3 is heavily linked to oncogenesis in various tissue types and accumulating evidence suggests that targeting JMJD3 as a therapeutic target may prove feasible and efficacious [12,13]. ...
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Objectives This study aimed to explore the effects and relative mechanism of JMJD3 on knee osteoarthritis (OA).Methods In this study, we first analyzed the expression of JMJD3 in OA cartilage using western blot and immunohistochemistry. In an in vitro study, the effects of GSK-J4, JMJD3 inhibitor, on ATDC-5 chondrocytes were evaluated by CCK-8 assay. Real-time PCR and western blot were used to examine the inhibitory effect of GSK-J4 on the inflammation and ECM degradation of chondrocytes. NF-κB p65 phosphorylation and nuclear translocation were measured by western blot and immunofluorescence. In the animal study, twenty mice were randomized into four experimental groups: sham group, DMM-induced OA + DMSO group, OA + low-dose GSK-J4 group, and OA + high-dose GSK-J4 group. After the treatment, hematoxylin–eosin and safranin O/fast green staining were used to evaluate cartilage degradation of knee joint, with OARSI scores for quantitative assessment of cartilage damage.ResultsOur results revealed that JMJD3 was overexpressed in OA cartilage and GSK-J4 could suppress the IL-1β-induced production of pro-inflammatory cytokines and catabolic enzymes, including IL-6, IL-8, MMP-9 and ADAMTS-5. Consistent with these findings, GSK-J4 could inhibit IL-1β-induced degradation of collagen II and aggrecan. Mechanistically, GSK-J4 dramatically suppressed IL-1β-stimulated NF-κB signal pathway activation. In vivo, GSK-J4 prevented cartilage damage in mouse DMM-induced OA model.Conclusions This study elucidates the important role of JMJD3 in cartilage degeneration in OA, and our results indicate that JDJM3 may become a novel therapeutic target in OA therapy.
... The biological functions of some identified genes are still not elucidated, which holds true for CCDC74A (coiled-coil domain containing 74A) and OR2T35 (olfactory receptor family 2 subfamily T member 35), for which no publication is available as of Apri 2019. Two other genes, ZNF417 and KDM6B, have been associated as part of a gene signature with cancer aggressiveness [32][33][34][35][36][37][38][39][40]. In a gene enrichment analysis, the Fanconi anemia (FA) pathway was indicated in addition to the above mentioned biological processes. ...
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In up to 30% of non-small cell lung cancer (NSCLC) patients, the oncogenic driver of tumor growth is a constitutively activated epidermal growth factor receptor (EGFR). Although these patients gain great benefit from treatment with EGFR tyrosine kinase inhibitors, the development of resistance is inevitable. To model the emergence of drug resistance, an EGFR-driven, patient-derived xenograft (PDX) NSCLC model was treated continuously with Gefitinib in vivo. Over a period of more than three months, three separate clones developed and were subsequently analyzed: Whole exome sequencing and reverse phase protein arrays (RPPAs) were performed to identify the mechanism of resistance. In total, 13 genes were identified, which were mutated in all three resistant lines. Amongst them the mutations in NOMO2, ARHGEF5 and SMTNL2 were predicted as deleterious. The 53 mutated genes specific for at least two of the resistant lines were mainly involved in cell cycle activities or the Fanconi anemia pathway. On a protein level, total EGFR, total Axl, phospho-NFκB, and phospho-Stat1 were upregulated. Stat1, Stat3, MEK1/2, and NFκB displayed enhanced activation in the resistant clones determined by the phosphorylated vs. total protein ratio. In summary, we developed an NSCLC PDX line modelling possible escape mechanism under EGFR treatment. We identified three genes that have not been described before to be involved in an acquired EGFR resistance. Further functional studies are needed to decipher the underlying pathway regulation.
... The expression level of the 11 genes was significantly upregulated after high temperature treatment during TSP and reached a similar level as that in MC. Of the 11 genes, lysine specific demethylase 6A was an interesting gene because Kdm6a (lysine demethylase 6A) and Kdm6b (Jmjd3) are the only two histone demethylases that activate gene expression via demethylating H3K27me3 to H3K27me2 or H3K27me1 (46). Epigenetic regulation in response to temperature effects has long been proposed to be associated with TSD or GSDϩTE (34). ...
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Fish sex-determining mechanisms can be classified as genotypic (GSD), temperature (TSD), or genotypic plus temperature effects (GSD+TE). Previous studies have shown that culturing water temperature during thermosensitive periods (TSP) could affect the expression of many genes in the gonad in some fish. However, few studies have focused on gene expression changes in the brain after temperature treatment during TSP in fish species. In this study, three families were developed by crossing XX neomales with XX females and one of them was used for transcriptome analysis. The results showed that a total of 105, 3164 and 4666 DEGs were respectively obtained in FC (female control) vs. FT (high temperature-treated females at TSP), FC vs. MC (male control), and MC vs. FT comparison groups. By profiling analysis, we show that the mRNA expression levels of 16 differentially expressed genes (DEGs) exhibited significant downregulation or upregulation after high temperature treatment and reached a similar level as that in MC. Among the 16 DEGs, LOC100699848 (lysine specific demethylase 6A) and Jarid2 contained JmjC domain, showing the possible important role of JmjC domain in response to temperature treatment in Nile tilapia. Kdm6b (lysine demethylase 6B) and Jarid2 have been shown to play important roles in reptile TSD, showing the relative conservation of underlying regulation mechanisms between TSD in reptile and TSD or GSD+TE in fish species. Finally, the transcriptome profiling was validated by quantitative real-time PCR in nine selected genes. These results provide a direction for investigating the GSD+TE molecular mechanism in fish species.
... Aberrant epigenetic reprogramming plays a pivotal role in tumorigenesis [7]. Among epigenetic regulation factors, histone methyltransferases (HMTs) are frequently dysregulated in a spectrum of human tumors, which indicates that HMTs are potential therapeutic targets [8]. ...
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Background In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, the mechanisms of drug resistance remain elusive, limiting therapeutic efficacy. Here, we set out to explore the relationship between dynamic histone changes and the efficacy of cisplatin against OS. Results First, we found two histone demethylases associated with histone H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, and KDM6B that were upregulated after cisplatin treatment. Consistent with the clinical data, cisplatin-resistant OS specimens showed lower H3K27me3 levels than sensitive specimens. Then, we evaluated the effects of H3K27me3 alteration on OS chemosensitivity. In vitro inhibition of the histone methyltransferase EZH2 in OS cells decreased H3K27me3 levels and led to cisplatin resistance. Conversely, inhibition of the demethylases KDM6A and KDM6B increased H3K27me3 levels in OS and reversed cisplatin resistance in vitro and in vivo. Mechanistically, with the help of RNA sequencing (RNAseq), we found that PRKCA and MCL1 directly participated in the process by altering H3K27me3 on their gene loci, ultimately inactivating RAF/ERK/MAPK cascades and decreasing phosphorylation of BCL2. Conclusions Our study reveals a new epigenetic mechanism of OS resistance and indicates that elevated H3K27me3 levels can sensitize OS to cisplatin, suggesting a promising new strategy for the treatment of OS. Electronic supplementary material The online version of this article (10.1186/s13148-018-0605-x) contains supplementary material, which is available to authorized users.
Jumonji domain-containing 3 (JMJD3/KDM6B) is a histone demethylase that plays an important role in regulating development, differentiation, immunity, and tumorigenesis. However, the mechanisms responsible for the epigenetic regulation of inflammation during mastitis remain incompletely understood. Here, we aimed to investigate the role of JMJD3 in the lipopolysaccharide (LPS)-induced mastitis model. GSK-J1, a small molecule inhibitor of JMJD3, was applied to treat LPS-induced mastitis in mice and in mouse mammary epithelial cells (MECs) in vivo and in vitro. Breast tissues were then collected for histopathology and protein/gene expression examination, and mouse MECs were used to investigate the mechanism of regulation of the inflammatory response. We found that the JMJD3 gene and protein expression were upregulated in injured mammary glands during mastitis. Unexpectedly, we also found JMJD3 inhibition by GSK-J1 significantly alleviated the severity of inflammation in LPS-induced mastitis. These results are in agreement with the finding that GSK-J1 treatment led to the recruitment of histone 3 lysine 27 trimethylation (H3K27me3), an inhibitory chromatin mark, in vitro. Furthermore, mechanistic investigation suggested that GSK-J1 treatment directly interfered with the transcription of inflammatory-related genes by H3K27me3 modification of their promoters. Meanwhile, we also demonstrated that JMJD3 depletion or inhibition by GSK-J1 decreased the expression of Tlr4 (Toll-like receptor 4) and negated downstream NF-κB (Nuclear Factor Kappa B) proinflammatory signaling, and subsequently reduced LPS-stimulated up-regulation of Tnfa, Il1b, and Il6. Together, we propose that targeting JMJD3 has therapeutic potential for the treatment of inflammatory diseases.
Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine 27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells.
The deregulation of epigenetic pathways has been implicated as a critical step in tumorigenesis including in childhood brain tumor medulloblastoma. The H3K27me3 demethylase UTX/KDM6A plays important roles in development and is frequently mutated in various types of cancer. However, how UTX regulates tumor development remains largely unclear. Here, we report the generation of a UTX-deleted mouse model of SHH medulloblastoma that demonstrates the tumor suppressor functions of UTX, which could be antagonized by the deletion of another H3K27me3 demethylase JMJD3/KDM6B. Intriguingly, UTX deletion in cancerous cerebellar granule neuron precursors (CGNPs) resulted in the impaired recruitment of host CD8⁺ T cells to the tumor microenvironment through a non-cell autonomous mechanism. In both mouse medulloblastoma models and in human medulloblastoma cells, we showed that UTX activates Th1-type chemokines, which are responsible for T cell migration. Surprisingly, our results showed that the depletion of cytotoxic CD8⁺ T cells did not affect mouse medulloblastoma growth. Nevertheless, the UTX/chemokine/T cell recruitment pathway we identified may be applied to many other cancers and may be important for improving cancer immunotherapy. In addition, UTX is required for the expression of NeuroD2 in precancerous progenitors, which encodes a potent proneural transcription factor. Overexpression of NEUROD2 in CGNPs decreased cell proliferation and increased neuron differentiation. We showed that UTX deletion led to impaired neural differentiation, which could coordinate with active SHH signaling to accelerate medulloblastoma development. Thus, UTX regulates both cell-intrinsic oncogenic processes and the tumor microenvironment in medulloblastoma. Our study provides insights into both medulloblastoma development and context dependent functions of UTX in tumorigenesis.
Epigenetic regulation of gene expression is integral to cell differentiation, development, and disease. Modes of epigenetic regulation—including DNA methylation, histone modifications, and ncRNA-based regulation—alter chromatin structure, promotor accessibility, and contribute to posttranscriptional modifications. In the cardiovascular system, epigenetic regulation is necessary for proper cardiovascular development and homeostasis, while epigenetic dysfunction is associated with improper cardiac development and disease.
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JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo, treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes.
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T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtypespecific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.
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Decreased epithelial cadherin (E-cadherin) gene expression, a hallmark of epithelial–mesenchymal transition (EMT), is essential for triggering metastatic advantage of the colon cancer. Genetic mechanisms underlying the regulation of E-cadherin expression in EMT have been extensively investigated; however, much is unknown about the epigenetic mechanism underlying this process. Here, we identified ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), a histone demethylase involved in demethylating di- or tri-methylated histone 3 lysine 27 (H3K27me2/3), as a positive regulator for the expression of E-cadherin in the colon cancer cell line HCT-116. We showed that inactivation of UTX down-regulated E-cadherin gene expression, while overexpression of UTX did the opposite. Notably, overexpression of UTX inhibited migration and invasion of HCT-116 cells. Moreover, UTX demethylated H3K27me3, a histone transcriptional repressive mark, leading to decreased H3K27me3 at the E-cadherin promoter. Further, UTX interacted with the histone acetyltransferase (HAT) protein CBP and recruited it to the E-cadherin promoter, resulting in increased H3K27 acetylation (H3K27ac), a histone transcriptional active mark. UTX positively regulates E-cadherin expression through coordinated regulation of H3K27 demethylation and acetylation, switching the transcriptional repressive state to the transcriptional active state at the E-cadherin promoter. We conclude that UTX may play a role in regulation of E-cadherin gene expression in HCT-116 cells and that UTX may serve as a therapeutic target against the metastasis in the treatment of colon cancer.
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Trimethylated histone H3 lysine 27 (H3K27me3) is linked to gene silencing, whereas H3K4me3 is associated with gene activation. These two marks frequently co-occupy gene promoters, forming bivalent domains. Bivalency signifies repressed but activatable states of gene expression and can be resolved to active, H3K4me3-prevalent states during multiple cellular processes, including differentiation, development and epithelial mesenchymal transition. However, the molecular mechanism underlying bivalency resolution remains largely unknown. Here, we show that the H3K27 demethylase UTX (also called KDM6A) is required for the resolution and activation of numerous retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse embryonic stem cells (ESCs). Notably, UTX loss in mouse ESCs inhibited the RA-driven bivalency resolution and activation of most developmentally critical homeobox (Hox) a–d genes. The UTX-mediated resolution and activation of many bivalent Hox genes during mouse ESC differentiation were recapitulated during RA-driven differentiation of human NT2/D1 embryonal carcinoma cells. In support of the importance of UTX in bivalency resolution, Utx-null mouse ESCs and UTX-depleted NT2/D1 cells displayed defects in RA-driven cellular differentiation. Our results define UTX as a bivalency-resolving histone modifier necessary for stem cell differentiation.
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Inhibiting class I histone deacetylases (HDACs) increases energy expenditure, reduces adiposity and improves insulin sensitivity in obese mice. However, the precise mechanism is poorly understood. Here, we demonstrate that HDAC1 is a negative regulator of brown adipocyte thermogenic program. HDAC1 level is lower in mouse brown fat (BAT) than white fat, is suppressed in mouse BAT during cold exposure or β3-adrenergic stimulation, and is down-regulated during brown adipocyte differentiation. Remarkably, overexpressing HDAC1 profoundly blocks, whereas deleting HDAC1 significantly enhances β-adrenergic activation-induced BAT-specific gene expression in brown adipocytes. β-adrenergic activation in brown adipocytes results in a dissociation of HDAC1 from promoters of BAT-specific genes, including uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), leading to increased acetylation of histone H3 lysine 27 (H3K27), an epigenetic mark of gene activation. This is followed by dissociation of the polycomb repressive complexes, including the H3K27 methyltransferase enhancer of zeste homologue (EZH2), suppressor of zeste 12 (SUZ12), and ring finger protein 2 (RNF2) from, and concomitant recruitment of H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) to UCP1 and PGC1α promoters, leading to decreased H3K27 trimethylation, a histone transcriptional repression mark. Thus, HDAC1 negatively regulates brown adipocyte thermogenic program, and inhibiting HDAC1 promotes BAT-specific gene expression through a coordinated control of increased acetylation and decreased methylation of H3K27, thereby switching transcriptional repressive state to active state at the promoters of UCP1 and PGC1α. Targeting HDAC1 may be beneficial in prevention and treatment of obesity by enhancing BAT thermogenesis.
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Progression from brown preadipocytes to adipocytes engages two transcriptional programs: the expression of adipogenic genes common to both brown fat (BAT) and white fat (WAT), and the expression of BAT-selective genes. However, the dynamics of chromatin states and epigenetic enzymes involved remain poorly understood. Here we show that BAT development is selectively marked and guided by repressive H3K27me3 and is executed by its demethylase Jmjd3. We find that a significant subset of BAT-selective genes, but not common fat genes or WAT-selective genes, are demarcated by H3K27me3 in both brown and white preadipocytes. Jmjd3-catalyzed removal of H3K27me3, in part through Rreb1- mediated recruitment, is required for expression of BAT-selective genes and for development of beige adipocytes both in vitro and in vivo. Moreover, gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight reduction and cold intolerance, respectively. Together, we identify an epigenetic mechanism governing BAT fate determination and WAT plasticity. INTRODUCTION
Background/Aim: Global increase in the trimethylation of histone H3 at lysine 27 (H3K27me3) has been associated with the differentiation of normal stem cells and cancer cells, however, the role of H3K27me3 in the control of cancer stem cells (CSCs) remains poorly understood. We investigated the impact of increased H3K27me3 on CSCs using a selective H3K27 demethylase inhibitor GSKJ4. Materials and Methods: The effect of GSKJ4 on the viability as well as on the self-renewal and tumor-initiating capacity of CSCs derived from the A2780 human ovarian cancer cell line was examined. Results: GSKJ4 induced cell death in A2780 CSCs at a concentration non-toxic to normal human fibroblasts. GSKJ4 also caused loss of self-renewal and tumor-initiating capacity of A2780 CSCs surviving GSKJ4 treatment. Conclusion: Our findings suggest that H3K27 methylation may have an inhibitory role in the maintenance of CSCs and that GSKJ4 may represent a novel class of CSC-targeting agents.
Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-kappa B and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C-C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment. (C) 2016 AACR.
The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor. However, there is limited information on the structure–activity relationship of this series of compounds. Moreover, there are few scaffolds reported as chelating groups for Fe(II) ion in Jumonji demethylase inhibitors development. To further elaborate the structure–activity relationship of selective JMJD3 inhibitors and to explore the novel chelating groups for Fe(II) ion, we initialized a medicinal chemistry modification based on the GSK-J1 structure. Finally, we found that several compounds bearing different chelating groups showed similar activities with respect to GSK-J1 and excellent metabolic stability in liver microsomes. The ethyl ester prodrugs of these inhibitors also showed a better activity than GSK-J4 for inhibition of TNF-α production in LPS-stimulated murine macrophage cell line Raw 264.7 cells. Taking together, the current study not only discovered alternative potent JMJD3 inhibitors, but also can benefit other researchers to design new series of Jumonji demethylase inhibitors based on the identified chelating groups.