Advances in Bioscience and Biotechnology, 2012, 3, 720-730 ABB Published Online October 2012 (
Modulation of cell death pathways in cancer stem cells:
Targeting histone demethylases
Ravi Thakur, Durga Prasad Mishra*
Cell Death Research Laboratory, Division of Endocrinology, Central Drug Research Institute, Lucknow, India
Email: *
Received 16 August 2012; revised 28 September 2012; accepted 4 October 2012
Cancer stem cells (CSCs) are tumor initiating cells
within the tumor mass; that play a critical role in can-
cer pathogenesis. CSCs regulate cancer cell survival,
metastatic potential, resistance to conventional radio-
chemotherapy, disease relapse and poor prognosis.
Recent studies have established that the drug resis-
tant cancers and cancer cell lines possess high stem
cell like traits compared to their drug sensitive coun-
terparts. Histone demethylases are recently been
linked to drug induced reversible tolerant state in
cancers. Lysine histone demethylases are enzymes
those demethylate lysines in histones and can act as
transcriptional repressors or activators. Apart from
histones other cellular proteins like E2F1, Rb, STAT3
and p53 are also regulated by methylation and de-
methylation cycles. In cancer cells these enzymes
regulate cell survival, migration, invasion, and pro-
liferation. This review summarizes the current pro-
gress of research on the role of histone demethylases
in support ing drug to lerant canc er stem cell state and
their pote ntial as a drug target.
Keywords: Cancer Stem Cells; Histone Lysine
Demethylases; Cell Death; LSD1; KDM5A
Cancer stem cells (CSCs) represent a small population of
cells existing within the tumor mass and possess many
characteristics of normal stem cells [1]. They can divide
indefinitely, renew themselves and differentiate into
various tumor forming cells. The existence of CSCs has
long been debated but now presence of such rare popula-
tion of cells is well documented in various cancer types
[1,2]. To date, the presence of cancer stem cells has been
reported in acute and chronic myeloid leukemia, brain,
head and neck, lung, breast, pancreatic, gastrointestinal,
colon, prostate and skin cancers [3-15]. Standard radio-
therapy and chemotherapy is effective against most of
the cancer cells but cancer stem cells are highly resistant
to these therapies and remain viable post treatment [15-
17]. Among other cancer cells these cells are present as a
very small population though, they are believed to induce
tumor relapse, sometimes many years after the “success-
ful” treatment of the primary tumors [18-22]. There are
many ways by which a cancer stem cell escapes cell
death. The differentiation status of a cell is an important
intrinsic factor while components of microenvironment
such as secreted survival factors, adhesion-mediated
apoptosis resistance and hypoxic environment are im-
portant extrinsic factors regulating CSC survival [23-29].
CSCs are also responsible for the enhanced migratory
and metastatic potential of cancer cells [2]. During me-
tastasis cancer cell detaches itself from cancer mass and
resists cell death activation after detachment, a process
known as anoikis [30-33]. Epithelial to mesenchymal
transition (EMT) is an important step in metastasis of
various cancers; it is characterized by transition of a cell
to a much invasive, elongated mesenchymal form from a
less invasive epithelial form [2]. Recent evidences indi-
cates that CSC state, chemo-resistance and EMT path-
ways are somehow linked and activation of one induces
other one and vice-versa [34-39]. The acquired drug tol-
erant stem cell state in many cancers was found reverse-
ble once drug treatment is discontinued, indicating the
role of epigenetic mechanisms in chemo-resistance and
disease relapse. Various pharmacological inhibitors of
epigenetic modifiers like histone deacetylases (HDACs),
DNA methyltransferase (DNMTs), have shown promis-
ing results in cancer therapy [40,41]. Recently, a group
of epigenetic modifiers known as histone demethylases
have been the focus o f in tense investig ation for th eir role
in carcinogenesis [42].
Amongst this group, lysine histone demethylases are
protein lysine demethylases, which act on histone and
non-histone proteins [43,44]. Major function of this group
of enzymes is to mediate epigenetic regulation of gene
transcription at the chromatin level [44]. Histone de-
methylases have important role in various cellular proc-
*Corresponding a uthor.
R. Thakur, D. P. Mishra / Advances in Bioscience and Biotechnology 3 (2012) 720-730 721
esses like cell cycle progression, nuclear hormone medi-
ated and NF-kB signalling, p53 regulation, transcript-
tional regulation of Hox genes, fetoplacental develop-
ment, regulation of DNA replication and repair processes
[45,46]. Histone demethylases are often found to be
up-regulated in lung, colon, breast, prostate cancers and
retinoblastomas [47,48]. Hyperactivity of histone de-
methylases is responsible for enhanced cancer cell sur-
vival and poor patient prognosis [47,48].
Histone methylation, a critical event in the epigenetic
regulation is controlled by specific histone methyltrans-
ferases (adds methyl group to histones) and demethylases
(removes methyl group) [49]. Methylations of histone
H4 at lysine 20 (H4K20), histone H3 at lysines 9 (H3K9)
and 27 (H3K27), leads to transcriptional repression [49,
50]. While the methylations of lysine 4 (K4) and lysine
36 (K36) in histone H3 (H3K4, H3K36) are usually as-
sociated with transcription activation (Figure 1) [49,50].
The methyl groups in H3K4 are removed by histone de-
methylases LSD1, KDM1b, and JARID1A-1D, leading
to transcription repression, while methyl groups in
H3K27 are removed by KDM6b and in H3K9 by LSD1
resulting in transcription activation [49,51,52]. Histone
demthylases can either activate or repress the transcrip-
tional program by changing the histone code at the tran-
scription site [49]. Their role in activation and rep ression
is governed by the cell type, predominant signaling path-
ways and the cellular microenviron ment [53-55 ]. Histone
demethylase LSD-1, KDM5a and KDM5b are known to
maintain stem cell state in normal as well as cancer stem
Figure 1. Role of histone lysine demethylases in epigenetic
reprogamming. Histone lysinedemthylases (KDM) demethy-
lates H3K4me2 and H3K36me2 to repress and K3K9me2 and
H3K27me2 to activate transcription at a gene locus. KDM-
lysine demethylase.
cells and influence inductio n of drug resistant phenotype
in cancer cells [56]. Therefore, inhibition of histone de-
methylases could be a potent therap eutic target to inhibit
cancer stem cell growth as well as to sensitize chemo-
resistant cells to therapy/drug induced apoptosis.
Histone lysine demethylases promote tumorigenicity [47],
they modulates cell death pathways in two possible
ways-1) Epigenetic regulation by H3K4, H3K36 de-
methylation, thus repressing the transcription of pro-
apoptotic or anti-proliferation related genes and H3K9,
H3K27 demethylation, thereby activating anti-apoptotic
or proliferation related genes; 2) Modulation of cell sig-
naling pathways by direct lysine methylation mediated
activation and inactivation of targeted proteins. Histone
demethylases are known to repress mRNA expression of
Bcl2, p21, ERBB2, CCNA2, BRCA1, miR let-7e [56-59]
and regulate p53 functions [60,61].
2.1. Epigenetic Regulation of Cell Death and
Epigenetic regulation of cell death and proliferation by
histone lysine demethylases is mediated mainly through
repression of p21 by LSD1 and KDM5b [56]. In MLL-
AF9 leukemia stem cells LSD1and p21 are essential for
maintaining the properties of oncogenic potential and
self renewal. p21 is a cyclin-dependent kinase (cdk) in-
hibitor and is a key mediator of DNA damage induced
p53-dependent cell cycle arrest and apoptosis [62]. In
leukemic cells, p21 is necessary for self-renewal of leu-
kemia stem cells [63,64]. LSD1 and KDM5b regulate
mRNA expression of anti-apoptotic gene CDKN1 (p21)
[58]. LSD1 also regulates expression of cellular prolif-
eration genes CCNA2 and ERBB2 by b inding directly to
the promoters of these genes [58]. KDM5b interacts with
TFAP2C and Myc to form a complex leading to tran-
scriptional repression of p21 [56]. As LSD1 represses the
expression of p21, knockdown of LSD1 in MDA-MB
231 cell model decrease the occupancy of LSD1 on the
p21 promoter and significantly increase in the repressive
mark of methylated H3K9 on CCNA2 and ERBB2 pro-
moter regions [58]. CCNA2 encodes Cyclin A2 that
functions as CDK2 kinase activator and promotes pro-
gression of cell through G1/S and G2/M phases of cell
cycle [65]. ERBB2 (HER2) is a member of epidermal
growth factor (EGF) receptor family of receptor tyrosine
kinases. It forms heterodimer with other members of
EGF receptor family, stabilizing ligand binding and en-
hances downstream mitogen-activated protein kinase and
phosphatidylinositol-3 kinase mediated downstream sig-
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R. Thakur, D. P. Mishra / Advances in Bioscience and Biotechnology 3 (2012) 720-730
naling pathways [66]. Over-expression of cyclin A2 and
ERBB2 corresponds to a drug resistant or aggressive
phenotype of tumor cells [67,68].
LSD1 can also be linked to the aberrant regulation of
Wnt signaling pathways in cancer cells. Wnt signaling is
important to maintain cancer stem cell state in various
cancers [69]. Treatment of colon cancer cells with LSD1
oligoamine inhibitor SL111144 led to increases in
H3K4Me3, restoring expression of secreted frizzled-
related proteins 2 (SFRP2) [70]. SFRP2 ia a Wnt signal-
ing pathway antagonist and it enhances the expression of
the epithelial marker E-cadherin, through inhibition of the
expression of SLUG, TWIST and SNAIL [71]. SNAIL,
SLUG and Twist are transcription factors involved in the
epithelial mesenchymal transition (EMT) program [71].
KDM6b act on H3K27 and is responsible for activation
of anti-apoptotic gene Bcl2 transcription in hormone
dependent breast cancers [57]. Apart from normal anti-
apoptotic functions Bcl2 is thought to be involved in
resistance to conventional cancer therapies, suggesting
role of decreased apopto sis may play a role in the devel-
opment of cancer [72]. KDM5A-mediated H3K4 de-
methylase activity plays an importan t role in maintaining
the proliferative capacity of breast cancer cells through
repression of tumor suppressor genes, including BRCA1
[58]. Another histone lysine demethylase JARID1B leads
to repression of let-7e which then increases expression of
cyclin D1 [59]. Cyclin D1 is a target gene of mir let-7e
mediated gene regulation. JARID1B demethylase con-
tributes to tumor cell proliferation throu gh the epigenetic
repression of a tumor suppressor miR let-7 that has been
reported to be a direct regulator of RAS expression in
human cells [59,73]. In lung cancer patient samples, ex-
pression of RAS and let-7 showed reciprocal pattern,
which has low let-7 and high RAS in cancerous cells,
and high let-7 and low RAS in normal cells [74]. Other
targets of let-7 are some oncogenes like high mobility
group A2 (HMGA2) and MYC [74,75]. Histone lysine
demethylase mediated epigenetic gene regulation thus
can drive tumorigenisis in cancers and inhibit program-
med cell death to support cancer stem cells state.
2.2. Non-Epigenetic Regulation of Cell Death
and Proliferation
Non-epigenetic regulation by lysine histone demethy-
lases is mediated by their potential to demethylate vari-
ous cellular proteins [76]. E2F1-p53 axis is the major
target of non-epigenetic regulation of cell death and pro-
liferation [60,61]. p53 transcriptional activity is neces-
sary to inhibit cancer stem cells growth and proliferation
[60]. Histone lysine-specific demethylase LSD1 interacts
with p53 to repress p53-mediated transcriptional active-
tion and to inhibit p53 mediated apoptosis [60,61]. LSD1
removes both mono and di-methylation at K370 of p53
[60]. Mono-methylation K370me1 represses p53 func-
tion and prevents interaction of p53 with TP53BP1 (p53-
binding protein 1), thus represses p53-mediated tran-
scriptional activation [60,61] In p53 negative cells (p53-/-)
LSD1 removes methylation mark from E2F1 at lysine-
185 [60,61,77]. Lysine-185 methylation leads to E2F1
accumulation during DNA damage and activation of its
pro-apoptotic target genes p73 and Bim (Figure 2) [78].
E2F1 promotes DNA damage-induced apoptosis in p53
dependent as well as p53 independent manner [60,77].
LSD1 mediated demethylation leads to dysregulation of
the E2F1 function and pro motes survival in many cancer
cells [77].
2.3. KDM5A (JARID1A) and KDM1A (LSD1)
Support Drug Tolerant Cancer Stem Cell
Apart from specific mechanism and targets involved in
histone lysine demethylase mediated regulation of cell
proliferation and apoptosis, various studies link lysine
histone demethylases to cancer drug tolerant stem cell
state [56,79-81]. The Settleman lab generated erlotinib
resistant versions of PC9 lung cancer cells by exposing
these cells to media containing increasing concentrations
of erlotinib [79]. This drug tolerant state could be re-
versed after withdrawing the drug, suggesting a epige-
netic link behind this reversible erlotinib resistance [79].
In the erlotinib resistant population of PC9 cells, K DM5A
expression was increased, leading to decreased global
levels of H3K4me3 and H3K4me2 (Figure 3) [79].
Figure 2. General role of lysine histone demethylases in main-
taining cancer stem cell state. Cancer stem cells over-express
histone lysine demethylases and low expression is associated
with differentiated state. KDM-lysine demethylase.
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R. Thakur, D. P. Mishra / Advances in Bioscience and Biotechnology 3 (2012) 720-730 723
Figure 3. Histone lysine demethylases and cell death pathways.
LSD1 mediated non-epigenetic modulation of p53 and E2F
activity modifies cell death and proliferation pathways. LSD1
demetylates p53 and p21, thus inhibits transcription activity of
both transcription factors. Dimethylation at p53 is essential for
its binding to p53 binding protein and induce transcription of
pro-apoptotic gene. In presence of LSD1 p53 fails to trigger
cell death response. In presence of LSD1 E2F1 also fails to
trigger apoptosis. SET9 methylates E2FI to activate it and pro-
mote apoptosis. E2F-E2F1 transcription factor; SET9-SET do-
main containing (lysine methyltransferase) 7/9; P53BP-p53
binding protein; TP73-tumor protein 73; APAF1-Apoptotic pro-
tease activating factor 1; CASP3,7,8-Caspase 3,7,8; MAP3K5-
mitogen-activated protein kinase kinase kinase 5.
In an another study carried out by the Zhanq lab demon-
strated that pharmacological inhibition LSD1 specifically
kill cancer cells expressing plu ripotent stem cell markers
[80]. LSD1 inhibition led to the decrease in p roliferation
of pluripotent cancer cells including teratocarcinoma,
embryonic carcinoma, seminoma or embryonic stem
cells that express the stem cell markers Oct4 and Sox2
[80]. They also demonstrated that LSD1 inhibition has
minimum growth-inhibitory effects on non-pluripotent
cancer or normal somatic cells [80]. Similar kind of re-
sults were also been obtained in a study carried out in
MLL-AF9 Leukemia stem cells [64]. The study also
found that inhibition of LSD1 using tranylcypromine
analogs leads to differentiation of human AML cells
without affecting normal repopulating cells [81].
3.1. LSD1 Expression and Its Potential as a
Therapeutic Target in Various Cancers
LSD1 expression was found altered in many cancer types
[82]. In lung cancer over expression and nuclear local-
ization of LSD1 is associated with shorter overall sur-
vival of non-small cell lung cancer (NSCLC) patients
[82]. LSD1 disruption using siRNA or a chemical in-
hibitor pargyline, up-regulates epithelial marker E-cad-
herin and down-regulates mesenchymal markers Twist
and N-Cadherin, thus suppresses proliferation, migration
and invasion of A549, H460 and 293T cells [82].
In acute myeloid leukemia (AML) inhibition of LSD1
using tranylcypromine (TCP) increases H3K4me2 and
expression of myeloid-differentiation-associated genes
[83]. In combination with all-trans-retinoic acid (ATRA)
LSD1 inhibitor TCP leads to decrease in the engraftment
of human AML cells in NOD-SCID γ (with interleukin-2
(IL-2) receptor γ chain deficiency) mice [83]. Effect of
combination was better than the effect of either drug
alone [83] .
In prostate cancer LSD1 play an important role in An-
drogen receptor signaling. Androgen Receptor signaling
is essential for prostate cancer initiation and progression
[84]. Androgen deprivation therapy remains the standard
of care for treatment of advanced prostate cancer [84].
Inhibition of LSD1 using its pharmacological inhibitor
namoline blocks LSD1 demethylase activity in vitro and
in vivo [85,86]. Inhibition of LSD1 b y namoline leads to
the silencing of androgen receptor (AR)-regulated gene
expression and severely impairs androgen-dependent
proliferation in vitro and in vivo [85].
There are mixed reports on breast cancers, LSD1 ex-
pression is very low in most of the breast cancers. In a
study carried out by Wang et al. in MDA-MB 231 (ER
negative, PR negative) breast cancers cells revealed that
LSD1 is a negative regulator of cancer metastasis [87].
LSD1 forms a complex with NuRD (LSD1/NuRD) and
regulate the metastatic potential of breast cancer cells
[87]. NuRD complex has histone deacetylase activity.
Expression of LSD1 negatively co-relates with the ex-
pression of TGF-b, as TGFb signaling pathway is criti-
cally involved in epithelial-mesenchymal transitions and
tumor invasion, ectopic expression of LSD1 leads to
suppression of tum or inv asion and m igration [8 7]. A v ery
high expression of LSD 1 has been observed in ER nega-
tive breast cancers in a study carried out by Soyoung et
al. They further knocked down LSD1 in ER negative
cells using siRNA that resulted in growth retardation of
breast cancer cells in vitro [88]. Similar results were ob-
tained on LSD1 inhibition by pharmacological inhibitor
clorgyline or tranylcypromine [88]. The potential of
LSD1 as a therapeutic target in breast cancer is still ob-
In other cancers LSD1 expression is differentially high
in cancer tissue than normal tissue. This differential ex-
pression of LSD1makes it a promising target in treatment
of various cancer types.
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Copyright © 2012 SciRes.
3.2. Expression of Other Histone Lysine
Demethylases in Cancers and Their
Potential as Therapeutic Target
Histone lysine demethylase KDM2B express differen-
tially in various cancers [89,90]. In leukemia it acts as an
oncogene and its over-expression helps in leukemia de-
velopment and maintenance [89]. While in aggressive
brain tumors KDM2B expression is low and it imparts a
negative effect on cell size and cell proliferation [90]. In
bladder cancers FGF-2 signaling leads to up-regulation of
KDM2B. KDM2B up-regulation is essential for FGF-2
mediated cell proliferation, migration and angiogenesis
[55]. Expression of another histone demethylase KDM3A
was found up-regulated in r enal cell carcinoma and colon
cancer [91]. KDM3A regulates genes implicated in can-
cer cell growth, invasion, and survival [91]. KDM3A
knockdown in cells resulted in reduction of tumor growth
rate in mice xenograft model [91]. In nasopharyngeal
carcinoma KDM3A expression negatively correlates with
poor prognosis and is often found down-regulated in
aggressive tumors [92]. KDM4A and KDM4B were
found up-regulated in prostate cancer, while KDM4B
expression was high in renal carcinoma [93,94]. High
expression of KDM4C is associated with oncogenic pro-
gression in esophageal squamous cell carcinoma and
metastatic lung sarcomatoid carcinoma [96]. Various
gene amplifications of KDM4C were observed in Breast
cancer and desmoplastic medulloblastomas leading to its
over-expression in both cancer types [97,98]. KDM5A
expression was found altered only when cancer cells are
subjected to drug induced stress [79] (discussed previ-
ously) while KDM5B is over-expressed in breast cancers
and plays role of an oncogene; it represses various tumor
suppressor genes including BRCA1 [99,100]. In prostate
cancer tissues KDM5B expression was also found high
compared with benign prostate samples [101]. KDM6A
activity in bladder cancer is very low due to inactivating
mutations [102]. KD M6A function as a tumor suppresso r
[103]. KDM6B expression was found high in hodgkin’s
lymphoma and prostate cancer and has been reported to
rise further in metastatic prostate cancer [104,105]. An-
other demethylase KDM8 was reported to be over-ex-
pressed in breast cancers and it supports cancer cell pro-
liferation [106]. Table 1 summarizes expression of ly-
sine histone demetylases in various cancers.
Among all histone lysine demethylases LSD1, appears
to be a promising target in lung cancer, prostate cancer
and acute myeloid leukemia. KDM4A, KDM4B and
KDM5b could possibly be therapeutic targets in prostate
Table 1. Expresson of histone lysine demethylases in cancer.
Cluster Name Expression in cancer types Ref.
Overexpression in breast, small cell lung, colorectal, prostate, neuroblastoma,
and bladder cancer [82-87]
KDM2 KDM2A Reduced expression in prostate cancer and colon cancer
KDM2B Overexpression in Leukemia and bladder cancer, low expression in brain tumors. [55,89,90]
Overexpression in renal cell carcinoma and colon cancer. Low expression in
nasopharyngeal carcinoma. [91,92]
KDM3C Low expression in breast cancer [41]
KDM4 KDM4A Overexpression in prostate cancer [93]
KDM4B Overexpression in renal carcinoma [94]
Overexpression in esophageal squamous cell car cinoma and Metastatic lung
sarcomatoid carcinoma [95-98]
KDM5 KDM5A Overexpression in gastric cancer [41,42]
KDM5B Overexpression in Breast and prostate cancer [79,99]
KDM6 KDM6A Low expression in bladder cancer [103]
KDM6B Overexpression in Hodgkin’s Lymphoma and Prostate cancer [104,105]
KDM8 KDM8 Overexpressed in breast cancer [106]
(N.R.-Not reported)
R. Thakur, D. P. Mishra / Advances in Bioscience and Biotechnology 3 (2012) 720-730 725
cancers, while in case of breast cancer KDM8 and
KDM4C as possible targets seem promising.
Histone lysine demethylases were discovered in last
decade and their role in cancer and other biological func-
tion came into limelight only in the last 5 years. Histone
methylation modulates the structure and function of
chromatin [49]. The balance between the methylation
and demethylation of specific histone residues at gene
locus is critical for regulating gene expression. Still
much is not known about the targets of these enzymes,
also their role in various cancers is yet to be delineated.
Current literature limits only to their poten tial role in few
malignancies and in some cancer models to drug tolerant
cancer stem cell state. Prior to the therapeutic targeting,
their precise role in initiation, progression and spread/
metastasis must be d eciphered. Th erefore more thorough
insight is required to their biology in cancer and cancer
stem cells.
Histone demethylases work as erasures of histone code
and they also regulate function of various proteins by
lysine demethylation [43,44]. This group of enzyme is
known to regulate various cancer hallmarks; they par-
ticipate in self renewal, differentiation, anti-apoptotic,
migratory, and angiogenic pathways [45,46]. Histone
deacetylases another group of epigenetic enzymes func-
tion as erasures of lysine acetyl group at histones [107].
HDACs are also known to modulate various cancer
hallmarks and thus are an established group of therapeu-
tic targets [107]. Like HDACs, demthylases also modu-
late functions and expression o f versatile targets and this
makes them a good choice for development of cancer
therapeutics. There are various HDAC inhibitors cur-
rently under cancer clinical trials [107,108]. HDACs
removes acetyl group from histones and make DNA
more tightly packed around histones, and thus leads to
transcription repression (similar to demethylases) of
genes present at target site [108]. Like histone demethy-
lases, HDACs also modulate proteins non-epigenetically;
p53, E2F1 and STAT3 are common targets [108]. His-
tone demethylase inhibitors can be used in combination
with the HDAC inhibitors in cancer where both HDAC
and demethylase activities are high. HDAC inhibition
usually leads to E2F1 and p53 activation and STAT3
inactivation [108]. Therefore combination of both could
be an effective way to treat cancers. A recent study using
HDAC inhibitor vorinostat in combination with LSD1
inhibitor PCI-24781, reported that the combination in-
duced a synergistic apoptotic cell death in glioblastoma
multiforme cells [109]. A similar study in breast cancer
used HDAC inhibitor in combination with LSD1 and
LSD2 inhibitors, and found a synergistic effect only in
HDAC-LSD1 inhibitor combination [110]. Few specula-
tions can be made out of these studies: 1) HDAC inhibit-
tors and Lysine demethylase inhibitors could result in to a
synergestic combination; and 2) Probably not all combi-
nation will be highly effective.
KDM5A inhibitors could also be used in combination
with HDAC inhibitors or with standard therapeutic
agents to sensitize cancer cells to death. As h istone lysine
demethylases LSD1 and KDM5A play an important role
in cancer stem cell state and chemo-resistance their in-
hibitors could be a promising therapy [79-81].
Histone lysine demethylases inhibitors could be used
in combination with inhibitors of the pathways upregu-
lated in cancer and responsible for cancer stem cell state
and chemoresistance. Inhibitors of various cancer and
cancer stem cell related pathways, notch, receptor tyro-
sine kinase, hedgehog, wnt-β-catenin and mTOR can be
used in combination with each other and also with the
inhibitors o f hi st one demethylases [111-114].
The limited numbers of studies on histone lysine de-
methylases so far are suggestive of their potential as an
attractive drug target in cancer. Histone lysine demethy-
lases in some cases act as oncogenes and support cancer
growth and progression, while other cases act as tumor
suppressors and inhibit tumor growth. Most important
aspect of their function relate to cancer cell quiescence or
maintenance of cancer stem cell state and drug resistance.
Combination of histone demethylase inhibitors with tra-
ditional cancer therapy holds a huge potential for treat-
ment of various malignancies. However a thorough
mechanistic understanding of the basic biology of his-
tone lysine demethylases is imperative in gain ing a better
idea about their function in normal cellular processes as
well as carcinogenesis.
We wish to apologize to all colleagues whose work, because of lack of
space, could not be cited. We thank all the members of the DP Mishra
laboratory for helpful discussions. This work was supported by the
grants from the Defense Research and Development Organization
(GAP-0058) to DP Mishra. Ravi Thakur acknowledges the support by
the junior research fellowship from the Council of Scientific and In-
dustrial Research, New Delhi. The Communication Number of this
manuscript is 8325.
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