Arch. Pharm. Res.

(2019) 42:159–170 Online ISSN 1976-3786

https://doi.org/10.1007/s12272-019-01126-z Print ISSN 0253-6269

REVIEW

Targeting epigenetics for cancer therapy

Jong Woo Park1 • Jeung-Whan Han1

Received: 16 November 2018 / Accepted: 28 January 2019 / Published online: 26 February 2019
Ó The Author(s) 2019

Abstract Cancer can be identified as a chaotic cell state, Introduction

which breaks the rules that govern growth and reproduc-
tion, with main characteristics such as uncontrolled divi- According to the Centers for Disease Control and
sion, invading other tissues, usurping resources, and Prevention (CDC), cancer is the second leading cause of
eventually killing its host. It was once believed that cancer death in the top ten diseases, next to heart disease (Heron
is caused by a progressive series of genetic aberrations, and et al. 2012). Although we have accumulated vast knowl-
certain mutations of genes, including oncogenes and tumor edge about cancer, the statistics show that we are still far
suppressor genes, have been identified as the cause of from overcoming cancer. What makes cancer so hard to
cancer. However, piling evidence suggests that epigenetic overcome and how much do we know about cancer? Until
modifications working in concert with genetic mechanisms early 2000s, cancer was considered as a set of diseases
to regulate transcriptional activity are dysregulated in many caused by the accumulation of genetic mutations that
diseases, including cancer. Cancer epigenetics explain a control normal cellular homeostasis (Vogelstein et al.
wide range of heritable changes in gene expression, which 2013). Oncogenes and tumor suppressor genes (TSGs) are
do not come from any alteration in DNA sequences. the most well-known classes of genes implicated in cancer
Aberrant DNA methylation, histone modifications, and (Zhu et al. 2015). Proto-oncogenes, which normally help to
expression of long non-coding RNAs (lncRNAs) are key regulate cell growth or differentiation, can become onco-
epigenetic mechanisms associated with tumor initiation, genic by genetic mutation. Point mutation, chromosomal
cancer progression, and metastasis. Within the past decade, mutation, or copy number variation can lead to oncogene
cancer epigenetics have enabled us to develop novel activation through amplified expression or gain-of-function
biomarkers and therapeutic target for many types of can- from protein structural rearrangement. Translocation of the
cers. In this review, we will summarize the major epige- Philadelphia (Ph) chromosome in chronic myeloid leuke-
netic changes involved in cancer biology along with mia (CML) was discovered in 1960 (Nowell 2007).
clinical and preclinical results developed as novel cancer Translocation of proto-oncogene ABL at 9q34 to BCR on
therapeutics. chromosome 22 can produce a fusion gene called BCR-
ABL1, coding for a hybrid oncoprotein (Rowley 2001;
Keywords Cancer epigenetics  DNA methylation  Imbach 2014). BCR-ABL1 fusion oncoprotein is a con-
Histone modification  Epigenetic drugs stitutively active tyrosine kinase signaling protein, causing
the cell to divide uncontrollably and therefore develop
CML. Ras mutation is another most well-known gain-of-
function mutation identified in human cancer (Bos 1989;
& Jeung-Whan Han Fernández-Medarde and Santos 2011; Prior et al. 2012).
[email protected] RAS proteins (KRAS, NRAS, and HRAS) function as
1 GDP–GTP-regulated binary on–off switches, which regu-
Research Center for Epigenome Regulation, School of
Pharmacy, Sungkyunkwan University, Suwon 16419, late cytoplasmic signaling networks that are responsible for
Republic of Korea proliferation and cell survival (Bos 1989). Mutation of

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RAS proteins at 12, 13, or 61 codon enhances the binding gene expression in cancer through epigenetic pathways is
of GTP to the Ras protein, resulting in constitutive acti- very complex and is determined by chromatin structure
vation of Ras, which is associated with hyperproliferative changes, including DNA methylation, histone variants and
developmental disorders and cancer. Among three iso- various modifications, nucleosome remodeling, and small
forms, K-Ras has been shown to be the most frequently non-coding RNAs (Dawson and Kouzarides 2012). This
mutated isoform in most cancers. K-Ras gene is found to be review highlights the basic principles of epigenetic path-
mutated in 22% of all tumors, especially 90% of pancreatic ways involved in cancer development along with recent
tumors (Forbes et al. 2011). progress in clinical and preclinical studies targeting cancer
In contrast to oncogenes that are activated mainly by epigenetics.
gain-of-function mutations, tumor suppressors lose their
functions (loss-of-function mutation) through deletions or
point mutations. The retinoblastoma protein (RB) is a DNA methylation
tumor suppressor protein, which mutation was originally
identified in a rare childhood cancer retinoblastoma Epigenetic control is the way to determine which genes
(Knudson 1971). Rb can suppress cellular proliferation by should be turned on or off for normal development and in
regulating the E2F transcription factor, and the Rb/E2F response to the environment. They are mostly regulated by
pathway plays a critical role in the initiation of DNA groups of proteins called ‘epigenetic writers’, ‘epigenetic
replication (Nevins 2001). Later studies have identified readers’, and ‘epigenetic erasers.’ The writer is the enzyme
complex molecular functions of Rb through interactions that creates modifications around the genome. This change
with various proteins, and the Rb/E2F pathway was found is recognized by the reader. Finally, when the epigenetic
to be functionally inactivated in virtually all human cancers change is no longer needed, erasers can remove it.
(Chinnam and Goodrich 2011; Dyson 2016). DNA methylation was the first epigenetic modification
The functions of proto-oncogene proteins are to enhance found in humans in the early 1980s (Cooper 1983; Doerfler
cell division or inhibit cell death, while the functions of 1983). DNA methylation occurs in cytosines of CpG
tumor suppressors are normally to prevent cell division or (Cytosine-phosphate-Guanine) dinucleotide sequences to
cause cell death. Therefore, either gain-of-function muta- create 5-methylcytosine (5mC), which is catalyzed by
tions of proto-oncogenes or loss-of-function mutations of DNA methyltransferases (DNMTs) using S-adenyl
tumor suppressors could initiate cancer through uncon- methionine (SAM) as the methyl donor. Promoter regions
trolled cell growth and defective apoptosis (Zhu et al. containing higher GC content are called CpG islands
2015). After the Human Genome Project (HGP) was (CGIs). Hypermethylation of CGIs occurs in heterochro-
completed, we achieved a great deal in human genetics, matin regions, while hypomethylation commonly occurs in
and it became the starting point for human genomics actively expressed genes (Ohm et al. 2007; Meissner et al.
(Gonzaga 2012; Hood and Rowen 2013). Moreover, large- 2008). DNA methylation of CGIs can be found at many
scale cancer genome projects, such as The Cancer Genome different locations within the genome, including cen-
Atlas (TCGA), the Wellcome Trust Sanger Institute’s tromeres, telomeres, and inactive X-chromosomes (Vera
Cancer Genome Project, and the International Cancer et al. 2008; Pasque et al. 2018; Skakkebæk et al. 2018).
Genome Consortium (ICGC), have shed light on cancer There are three identified DNMT enzymes, which are
genomics. In addition, somatic mutations from thousands DNMT1, DNMT3A, and DNMT3B. DNMT3A and
of tumors have provided insights into cancer development DNMT3B are de novo methyltransferases that are
processes along with available therapeutic targets for can- responsible for the initial CpG methylation during
cer (McLendon et al. 2008; Hudson et al. 2010; Pleasance embryogenesis (Okano et al. 1998). DNMT1 maintains the
et al. 2010). methylation pattern during chromosome replication by
Achievements of HGP and other big studies have been preferential methylation on hemimethylated CpGs. After
powerful; however, the sequence itself does not explain CpG methylation, 5mC can become a platform for several
how the genome is packaged into chromatin and provide methyl-CpG-binding domain (MBD) proteins, such as
differential expression of genes for proliferation, develop- MBD1, MBD2, MBD3, MBD4, and MeCP2, for further
ment, and differentiation. Therefore, the current paradigm chromatin-templated processes (Mashimo et al. 2013).
to explain cancer development has now expanded to cancer There are other MBD-containing proteins, such as MBD5/
genetics and epigenetics. While cancer genetics focus on 6, SETDB1/2, and BAZ2A/B. The MBD proteins cooper-
abnormal gene expression, including altered protein ate with other epigenetic proteins like histone modifying
expression by either deletion or amplification mutations, enzymes or chromatin remodeling complexes at the 5mC
cancer epigenetics focus on the regulation of gene region and facilitate transcriptional repression (Du et al.
expression without changing the genome sequence. Altered 2015a).

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Targeting epigenetics for cancer therapy 161

Although direct removal of DNA methylation has not hematological malignancies (Cimmino et al. 2011; Naka-
been detected so far, there are a few ways to remove DNA jima and Kunimoto 2014).
methylation. First, passive DNA demethylation through Targeting of aberrant DNA methylation patterns has
steady dilution of methylation patterns can happen by been attempted, and two cytidine analogs, 5-azacytidine/
replication (Kriukiene et al. 2012). Secondly, ten–eleven vidaza (AZA) and 5-aza-20 -deoxycytidine/dacogen (DAC),
translocation (TET 1–3) enzymes can oxidize 5mCs to have been approved for the treatment of myelodysplastic
create 5-hydroxymethylcytosine (5hmC), and subsequently syndromes (MDS) by the FDA (Raj and Mufti 2006;
formyl-(5-fc) and carboxyl-(5caC) derivatives are formed. Santos et al. 2010). These two compounds form an irre-
The derivatives finally can be excised by the DNA repair versible covalent complex with DNMT1 and trigger pro-
protein thymine glycosylase (TDG) to be replaced by teasome-mediated DNMT1 degradation. Second-
unmodified cytosine via the base excision repair (BER) generation analog guadecitabine (SGI-110), which is an
pathway (Kohli and Zhang 2013). active metabolite of decitabine, is being tested in clinical
Aberrant DNA methylation patterns, both hyper- and trial for MDS and acute myeloid leukemia (AML) (Kan-
hypo-methylation, have been reported in many different tarjian et al. 2017). Although the role of the TET family in
types of cancer, including prostate, breast, gastric, liver, several cancers has been suggested from recent studies, a
lung, glioblastoma, and leukemia (Sun et al. 2010; Barbano TET protein inhibitor has yet to be tested for cancer
et al. 2013; Chao et al. 2013; Mehta et al. 2015; Liu and treatment.
Brenner 2016; Cecotka and Polanska 2018; Klughammer Writers, readers, and eraser enzymes for DNA methy-
et al. 2018). First cancer implication was the global lation and inhibitors are summarized in Table 1.
hypomethylation at CpG sites of DNA repetitive elements
identified in tumor cells (Bedford and van Helden 1987;
Lin et al. 2001). Loss of imprinting at the insulin-like Histone modification-lysine acetylation
growth factor 2 (IGF2) gene locus is frequently observed in
cancer and is provided as a colon cancer diagnosis (Cui DNA within eukaryotic cells is packaged as chromatin, and
et al. 2002). Conversely, hypermethylation of specific the histone octamer is the central component of the
genes have also been identified to explain the role of nucleosomal subunit. The histone subunit in the nucleo-
DNMTs in tumorigenesis. Hypermethylation of CpG some possesses a characteristic tail, which contains specific
islands in TSG promoters, including Braca1, Rb, or p53 amino acid residues for covalent posttranslational modifi-
promoters, leads to inactivation of each protein and can cations (PTMs), such as acetylation, methylation, phos-
enhance cancer development (Rideout et al. 1991; Sakai phorylation, ubiquitylation, sumoylation, or ADP
et al. 1991; Baldwin et al. 2000). Alteration of normal ribosylation. Each epigenetic PTM cooperates to regulate
DNA methylation has been well profiled for over 25 years chromatin states.
of epigenetic studies and provides its application for Histone acetylation is crucial for active gene transcrip-
diagnostic and therapeutic targets (Heyn and Esteller tion to influence the compaction state of chromatin by
2012). Although the exact cause of deregulated DNA neutralizing basic charges on unmodified lysine residues,
methylation patterns in cancer is not yet well established, decreasing the electrostatic interaction between negatively
an accumulation of data has shown that either mutation or charged DNA and histones. Histone acetylation occurs on
overexpression of DNMT proteins and MBD protein is the lysine residue, balanced by two enzymes: histone
correlated with tumorigenesis (Du et al. 2015b; Spencer acetyltransferase (HAT) and histone deacetylases (HDAC).
et al. 2017). In addition, several reports have emerged that There are primarily three families of HAT enzymes,
mutations of TET family genes were found in numerous including GNAT family (Gcn5, PCAF, Hat1), MYST

Table 1 Epigenetic drugs against DNA methylation changes

Writer (DNMTs) Reader (MBD family) Eraser (TET family)

Enzyme DNMT1, DNMT3a, DNMT3b MBD1, MBD2, MBD3, MBD4, MeCP2, MBD5/6, SETDB1/2, BAZ2A/B TET1, TET2, TET3
Drugs 5-azacytidine (approved)
5-aza-20 -deoxycytidine
(approved)
SGI-110 (clinical trials)
Enzymes for the drug target are highlighted in bold

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162 J. W. Park, J.-W. Han

family (MOZ/Morf, Ybf2, Sas2, Tip60), and CBP/P300 Acetylated histone can serve as a binding site for reg-
family (p300/CBP, Taf1) (Marmorstein and Roth 2001). ulatory factors, chromatin-remodeling complexes, and
These enzymes are also known to acetylate hundreds of especially for bromodomain-containing proteins, which are
other proteins besides histones, such as p53, sTAT3, known as histone acetylation readers. The human genome
GATA, etc., and have numerous biological functions, encodes 61 bromodomains present in 46 proteins, which
including regulation of protein stability, DNA binding are HATs, histone methyltransferases (HMTs), and tran-
affinity, and protein interactions (Spange et al. 2009). As scription initiation factors. Among these BRD proteins,
epigenetic erasers, 18 HDAC isoforms have been identified Bromodomain and extra-terminal (BET) proteins (BRD2,
in humans. Class I (HDACs 1, 2, 3, 8), Class IIa (HDACs BRD3, BRD4, BRDT) are highly associated with several
4, 5, 7, 9), Class IIb (HDACs 6, 10), and Class IV types of cancer (Padmanabhan et al. 2016). Small molecule
(HDAC11) are classical HDAC families that require a zinc triazolodiazepine-based inhibitors of the BET bromod-
ion (Zn2?) for their actions, whereas Class III HDACs omain, JQ1 and I-BET, were first developed (Pérez-Salvia
(SIRT1 to 7) require NAD? and are Zn2?-independent and Esteller 2017). They selectively bind to bromodomains
(Zhang et al. 2015). Aberrant histone lysine acetylation BD1 and BD2 of the BET family. BET inhibitors have
patterns, especially loss of histone H4 lysine (K) 16 shown great efficacy against human and murine MLL-fu-
acetylation, have been reported as a common hallmark of sion leukemic cell lines and mouse leukemia models. From
human cancer (Fraga et al. 2005). There are numerous further mechanistic studies, BET inhibition has been shown
reports showing involvement of HAT mutation or loss-of- to suppress cancer through inhibition of Myc expression,
function with many diseases, including cancer. Truncation targeting JAK-STAT, NF-jB pathway, and p53 acetylation
mutations and in-frame insertion mutations of EP300 have (Chan et al. 2015; Huang et al. 2017; Xu and Vakoc 2017).
been identified in several different cancers (Gayther et al. Currently, many different BET inhibitors are in clinical
2000). Further, it has been reported that the genes for p300, trial phase I or II for various different types of cancers.
CBP, MOZ, and MORF are rearranged in recurrent leu- Enzymes for histone acetylation, deacetylation, and readers
kemia-associated chromosomal abnormalities (Yang are summarized in Table 2.
2004). Although involvement of dysregulated HAT in
many diseases is becoming clear, clinical application of the
HAT inhibitor was not successful. Histone modification-lysine and arginine
In addition to histone deacetylation, HDACs have other methylation
roles in association with several transcription factors,
tumor suppressors, and oncogenes. For example, HDAC1 Another well-known histone modification is histone
forms a complex with Rb and E2F transcription factors and methylation on arginine and lysine residues. Different from
regulates gene expression of the cell cycle (Brehm et al. histone acetylation, methylation does not change the
1998; Kennedy et al. 2001). Moreover, increased expres- physical interaction between DNA and histone by neu-
sion of HDAC family proteins has been observed in many tralizing the histone charge. Further, methylation of
cancers, including B cell acute lymphoblastic leukemia specific lysine or arginine residues refers to either an active
(ALL) and T cell ALL, indicating the role of histone or repressive gene expression. Lysine methylation can exist
acetylation in various leukemogenesis (Moreno et al. 2010; in a mono-, di-, or tri-methylated state, implying the
Tao et al. 2013). Although HAT inhibitors were not clin- complexity of the regulatory mechanisms. Generally, H3
ically successful, HDACs have become great targets for lysine 4 (H3K4), H3K36, and H3K79 methylation is cor-
anticancer agents. Five classes of compounds—(I) hydrox- related with active gene expression, while di- and tri-
amic acids; (II) short chain fatty acids; (III) benzamides; methylation of H3K9, H3K27, and H3K20 are linked to
(IV) cyclic tetrapeptides; and (V) sirtuin inhibitors—are gene repression (Vermeulen et al. 2010).
currently developed as anticancer reagent, and they are Similar to other epigenetic modifications, histone
either isoform-selective or pan-inhibitors. Among hydrox- methylation is also regulated by writer (lysine methyl-
amates, SAHA, Belinostat and Panobinostat are approved transferases: KMTs), reader, and eraser (lysine demethy-
for T cell lymphoma. Romidespsin is a cyclicpeptide lases: KDMs) proteins. KMTs are comprised of 51 SET
HDAC inhibitor which is approved for cutaneous T cell (Su (var)3-9, Enhancer of Zeste, Trithorax) domain KMTs
lymphoma (CTCL) and peripheral T-cell lymphoma and one non-SET domain lysine HMT, known as DOT1L
(PTCL). The short chain fatty acid, Valproic acid, is (Qian and Zhou 2006). DOT1L contains a catalytic
approved for epilepsy. Many other classes of HDAC domain, which is structurally related to the domains of
inhibitors are in different clinical stages for various cancers protein arginine methyltransferases (Nguyen and Zhang
(Eckschlager et al. 2017). 2011). SET-domain proteins transfer a methyl group from
S-adenosyl-L-methionine (SAM) to the amino group of a

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Targeting epigenetics for cancer therapy 163

Table 2 Epigenetic drugs against histone acetylation changes

Writer (HATs) Reader (BRD family) Eraser (HDACs)

Enzyme GNAT family (Gcn5, PCAF, Hat1) BET proteins (BRD2, BRD3, BRD4, BRDT) Class I (HDACs 1, 2, 3, 8)
MYST family (MOZ/Morf, Ybf2, Sas2, Tip60) Class IIa (HDACs 4, 5, 7, 9)
CBP/P300 family (p300/CBP, Taf1) Class IIb (HDACs 6, 10)
Class IV (HDAC11)
Class III HDACs (SIRT1 to 7)
Drugs JQ1 (preclinical), I-BET762(Clinical trials) Belinostat (approved)
SAHA (approved)
Romidepsin (approved)
Valproic acid (approved)
Enzymes for the drug target are highlighted in bold

lysine residue on the histone or other protein, leaving a gene expression, but LSD1 can stimulate transcription
methylated lysine residue and the cofactor byproduct through interaction with the androgen receptor (Metzger
S-adenosyl-L-homocysteine (SAH). Most KMTs can et al. 2005). Several LSD1 inhibitors, such as ORY-1001 or
methylate several non-histone proteins, including p53, GSK2879552, have been developed and are under clinical
PCNA, STAT3, RARa, E2F1, FOXO3, DNMT1, and trial for AML treatment (Maes et al. 2015).
KMT1c (Moore and Gozani 2014). KDMs are comprised Similar to any other PTMs, histone lysine methylation
of two families of proteins based on the organization of can serve as a recognition site for the ‘reader’ or effector
their catalytic domains and the type of oxidative mecha- proteins. The malignant brain tumor (MBT) domain pro-
nisms for the demethylation reaction. The first group is the tein, PHD (plant homeodomain) proteins, chromodomain
Jumonji (Jmjc) domain-containing KDM family, which proteins, PWWP domain, and WD40 repeat proteins are
utilizes 2-oxoglutarate (2-OG; a-ketoglutarate) as a co- identified as histone lysine methylation readers (Herold
factor. The second group is KDM1A (LSD1, BHC110, et al. 2011). The inhibitor of growth (ING) family of tumor
AOF2) and KDM1B (LSD2), which utilizes flavin adenine suppressor genes (ING1-5) contains a C-terminal PHD,
dinucleotide (FAD) as a co-factor for demethylation which is known to preferentially bind di- and tri-methy-
activity. lated H3K4 and mediate many cellular processes (Cham-
Aberrant histone lysine methylation patterns have been pagne and Kutateladze 2009). Heterochromatin protein 1
identified in various human cancers. For example, low (HP1) is another example of a methyl-lysine reader. Three
levels of H3K4me2 correlated with low survival rates in isoforms of HP1 can interact with methylated H3K9 via its
both lung and kidney cancers and was also associated with chromodomain. Much evidence has shown that not only
adverse prognosis in non-small cell lung carcinomas alteration of histone modifying enzyme levels, but also
(NSCLC), hepatocellular carcinomas (HCC), and breast alteration of methyl-lysine reader expression has cancer
cancers (Barlési et al. 2007; Elsheikh et al. 2009; Seligson implications. For example, downregulation of HP1a has
et al. 2009). Either up- or down-regulated KMTs frequently been linked to the higher invasive potential of breast cancer
found in cancer and KDMs are involved in tumorigenesis cells and papillary thyroid carcinoma (Wasenius et al.
by several other mechanisms, including alteration of his- 2003; Norwood et al. 2006; De Koning et al. 2009).
tone or non-histone protein methylation (Varier and Tim- Alterations in histone lysine methylation are tightly
mers 2011; Colón-Bolea and Crespo 2014). Dysregulation linked to the development of cancer and are suggested as
of H3K27me3 is frequently observed in many types of potential cancer therapeutic targets. Many KMT inhibitors,
cancers, and overexpression of EZh2 or mutations in the such as DOT1L, EZH2, and SUV 39H1 inhibitors, are in
SET domain of EZH2 have been reported in lymphomas, preclinical or clinical trials. Many groups have developed
causing an increase of H3K27me3 (Pawlyn et al. 2017; EZH2 inhibitors, and among them, EPZ-6438 is in phase
Nienstedt et al. 2018). The histone demethylase LSD1 I/II trial for refractory B-cell lymphoma (Knutson et al.
(KDM1A) is highly expressed in several cancers and is 2014). In addition, the DOT1L inhibitor EPZ-5676 is in
specifically required for terminal differentiation of phase I clinical trial for refractory AML and ALL (Lillico
hematopoietic cells (Sprüssel et al. 2012). By histone et al. 2018; Stein et al. 2018). However, the search for
H3K4 1/2 demethylase activity, LSD1 (KDM1A) represses KMT or KDM inhibitors is still in its very first stages.

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Histone arginine methylation is similar to lysine to H3R17me2a loss, suggesting that it is responsible for
methylation in many ways. Protein arginine methyltrans- removing this methyl mark (Denis et al. 2009). However,
ferases (PRMTs) also utilize SAM to transfer a methyl PADIs catalyze the deimination of arginine; therefore, they
group to the guanidine nitrogen atoms of arginine to form are not considered as ‘‘true’’ demethylases.
methylarginines and SAH. There are three different forms As epigenetic readers of arginine methylation, Tudor
of methylarginines: x-NG-monomethylarginine (MMA), domain-containing proteins, such as SMN (Survival of
x-NG,NG-asymmetric dimethylarginine (aDMA), and motor neuron), SPF30 (Splicing factor 30), and TDRD1/2/
u-NG,N0 G-symmetric dimethylarginine (sDMA). PRMTs 3/6/9/11, have been identified to interact with methyl-
can be subcategorized into three groups by their catalytic arginine residues (Gayatri and Bedford 2014). However,
activity; type I (PRMT1, PRMT2, PRMT3, PRMT4, the biological role of the interaction between these two is
PRMT6, and PRMT8) and type II (PRMT5 and PRMT9) still unclear.
enzymes initially forms MMA as an intermediate before Aberrant expression of PRMT or dysregulation of
the establishment of aDMA or sDMA, respectively, while PRMT activity are associated with several diseases,
type III (PRMT7) enzymes only catalyze to form MMA including many types of cancers. For example, PRMT1 is
(Yang and Bedford 2013). Generally, H4R3me2a, the major PRMT, which is responsible for 90% of arginine
H3R2me2s, H3R17me2a, and H3R26me2a are correlated methylation, and it is upregulated in breast cancer, bladder
with active gene expression, while H3R2me2a, cancer, pediatric ALL, etc. (Yoshimatsu et al. 2011; Zou
H3R8me2a, H3R8me2s, and H4R3me2s are linked to gene et al. 2012). Most other PRMTs are also found to be
repression. PRMTs also can methylate many non-histone upregulated in various types of cancers; as a result, PRMTs
proteins that have arginine- and glycine-rich (GAR) motifs. are attractive cancer targets. Recently, a few PRMT inhi-
RNA-binding proteins (RBPs), Tumor suppressor bitors, such as the PRMT5 selective inhibitor
53-binding protein 1 (53BP1), and many other proteins (EPZ015666), have been generated and demonstrate
have been identified as substrates for PRMTs, and arginine promising therapeutic results against specific cancer types
methylation of these proteins is involved in various bio- in pre-clinical trials (Chen et al. 2017). Enzymes for his-
logical processes, such as transcription, cell signaling, tone methylation, demethylation, and readers are summa-
mRNA translation, DNA damage signaling, receptor traf- rized in Tables 3 and 4.
ficking, protein stability, and pre-mRNA splicing (Wei
et al. 2014).
Arginine methylation is a very stable modification; Histone modification-phosphorylation,
therefore, the existence of direct arginine demethylases is ubiquitination, and histone variant
still controversial. Jumonji domain-containing protein,
JmjD6, was reported to demethylate H3R2me2 and Protein phosphorylation is a very important PTM involved
H4R3me2, but later it was identified as a lysine hydroxy- in many cellular processes. Proteins with specific amino
lase (Webby et al. 2009). Moreover, a recent study showed acid residues, such as serine, threonine, and tyrosine resi-
that one of peptidylarginine deiminases (PAIDs) protein dues, are phosphorylated by a protein kinase by the addi-
PADI4 was recruited to the pS2 promoter region just prior tion of a covalently bound phosphate group.

Table 3 Drugs against histone lysine methylation changes

Writer (KMTs) Reader Eraser (KDMs)

Enzyme KMT1 (SUV 39H1, SUV 39H2, G9a, GLP, SET DB1, SET DB2) MBT family KDM1 (KDM1A, KDM1B)
KMT2 (MLL 1–5, hSET1A, hSET1B, ASH2) PHD fingers proteins KDM2 (JHDM1A, JHDM1B)
KMT3 (SET2, NSD1, SMYD1-3) Chromodomain proteins KDM3 (JHDM2A, JHDM2B)
KMT4 (DOT1L) PWWP domain proteins KDM4 (JMJD2A-2D)
KMT6 (EZH1, EZH2) WD40 repeat proteins KDM5 (JARID1A-1D)
KMT7 (SET7/9) KDM6 (UTX, JMJD3)
KMT8 (PRDM2/RIZ1) KDM7 (JHDM1D, PHF2, PHF8)
Drugs EPZ6438 (phase I/II) ORY-1001 (phase I/IIa)
EPZ5676 (phase I) GSK2879552 (phase I)
Enzymes for the drug target are highlighted in bold

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Targeting epigenetics for cancer therapy 165

Table 4 Drugs against histone arginine methylation changes

Writer (PRMTs) Reader Eraser

Enzyme PRMT1, PRMT2, PRMT3, PRMT4, PRMT5, PRMT6, PRMT7, PRMT8, PRMT9 Tudor domain proteins JmjD6
PAID
Drugs EPZ015666 (preclinical)
Enzymes for the drug target are highlighted in bold

Phosphorylation alters the structural conformation of a enzymes (DUBs) identified, and histone ubiquitination
protein, causing the target protein to become either acti- plays critical roles, including transcription, maintenance of
vated or deactivated. Protein kinases and phosphatases chromatin structure, and DNA repair (Cao and Yan 2012).
work independently and balance modifications to regulate H2Bub is highly associated with active gene expression,
the function of proteins. The most well-characterized his- while H2Aub plays a role in transcriptional silencing with
tone phosphorylation is H3S10. S28 and T11 phosphory- other repressive histone modifying enzyme complexes,
lation are known for transcriptional regulation and mitosis. such as polycomb repressive complex 1 (PRC1) (Minsky
Aurora B kinase, mitogen and stress-activated protein et al. 2008; Zhou et al. 2008). Conversely, H2A DUBs are
kinases 1 and 2 (MSK1 and MSK2), Ribosomal s6 kinase 2 often required for gene activation, indicating the impor-
(RSK2) IjB kinase-a (IKK-a), or PIM1 kinase can phos- tance of histone ubiquitination in gene expression (Joo
phorylate H3S10 in a DNA-context manner upon different et al. 2007; Zhu et al. 2007). Histone ubiquitination also
stimuli for immediate-early gene expression (Nowak and plays an important role in DNA damage. When DNA
Corces 2004). In fact, several studies reported that Aurora damage causes DNA double-strand breaks (DSB), histone
B is overexpressed in a variety of human cancers, partic- variant H2AX is rapidly phosphorylated and recruits DNA
ularly in colorectal and breast cancer (Ota et al. 2002; damage response regulators followed by subsequent
Tanaka et al. 2008). Histone phosphorylation, in coopera- recruitment of histone ubiquitin ligases RNF8 and
tion with other histone modifications, plays a crucial role in RNF168, which catalyze the K63-linked polyubiquitination
DNA damage response pathways and participates in chain formation of histone H2A and H2AX (Uckelmann
recruitment of downstream DNA damage response and and Sixma 2017). Aberrant histone ubiquitination, such as
repair proteins, as well as in the amplification of DNA down-regulated H2Aub and H2Bub, was found in several
damage signals. The histone H2A variant, H2AX, is cancers (Zhu et al. 2007; Prenzel et al. 2011). To date,
rapidly phosphorylated at S139 by ATM, DNA PK kinases, there are no therapeutic reagents targeting ubiquitination or
or ATR upon DNA damage stresses and spread over deubiquitination. Very little is known about histone mod-
megabases from the break site, which serves as a platform ification through the small ubiquitin-related modifier
for recruiting other DNA damage response proteins, (SUMO) or neddylation. SUMO shares 18% identity with
including 53BP1 (p53-binding protein 1), BRCA1, and ubiquitin, and NEDD8 is 90% homologous to ubiquitin.
NBS1 (Turinetto and Giachino 2015). H2AX gene is fre- Histone H4 can be modified by SUMO family proteins and
quently lost in cancer, and H2AX deficiency can lead to can associate with transcriptional repression through
increased sensitivity to ionizing radiation, which exhibit recruitment of HDAC1 and HP1 (Shiio and Eisenman
genomic instability and enhanced susceptibility to cancer 2003). Histone neddylation to H2A antagonizes H2A
(Georgoulis et al. 2017). However, epigenetic drugs tar- ubiquitination, which negatively regulates DNA damage
geting histone phosphorylation have yet to be established. repair pathways (Li et al. 2014). Although SUMO or
Ubiquitin is a small (8.5 kDa) regulatory protein, and Nedd8 share a similar structure with ubiquitin, they play
ubiquitination is the addition of ubiquitin to the lysine distinctive epigenetic roles in cooperation with other
residue of a substrate protein. The most well-known role of modifiers, indicating the complexity of regulating the epi-
protein ubiquitination is to degrade target protein primarily genetic process.
via the proteasomal degradation pathway (Swatek and Histone variants are proteins that substitute for the core
Komander 2016). Histones, especially H2A and H2B, are canonical histones (H3, H4, H2A, H2B) in nucleosomes in
well-known substrates for ubiquitination. All four histones eukaryotes and often confer specific structural and func-
and linker histone H1 can be ubiquitinated, and a single tional features. Unlike epigenetic regulation of ‘canonical’
ubiquitin moiety conjugated to H2A-K119 (ubH2A) and histones through posttranslational modification, histone
H2B k120 (ubH2B) is the most dominant form. There are variants work through specific deposition and removal
several histone ubiquitin ligases and deubiquitinating machineries. They have important roles in early embryonic

123
166 J. W. Park, J.-W. Han

A MBD

DNMT TET
DNMT1 inhibitor

Me Me Me Me Me Me Me Me Me

Exon Exon Repeat

B Methyl-
Lysine Binding
EZH2 inhibitor proteins KDM1 inhibitor BET inhibitor
DOT1L inhibitor

HDAC inhibitor
KMT KDM

ME BRD

DUB HAT HDAC

E3
Lig Phos-
Ub Kinase
AC phatase
P

ME

PRMT
Tudor- Canonical Histone
Domain
proteins

Histone variants

Fig. 1 Graphic summary of epigenetic alterations involved in cancer and available drugs targeting epigenetic mechanisms. a Tumorigenesis
through aberrant methylation of CpG islands. DNA methylation can be written by DNMTs (in blue), recognized by MBD proteins (in green) and
erased by TET proteins (in red). Epigenetic drugs targeting DNMT1 are approved by the FDA. b Tumorigenesis through aberrant histone
modifications. Writers of each histone modification such as histone lysine methyltransferase (KMT), histone acetyltransferase (HAT), ubiquitin
E3 ligases (E3 lig), protein arginine methyltransferase (PRMT), kinase are shown in blue. Readers such as methyl-lysine binding protein, tudor
domain protein, bromodomain and extra terminal domain family member (BRD) are shown in green. Erasers such as histone deacetylase
(HDAC), histone lysine demethylase (KDM), and deubiquitinating enzyme (DUB), phosphatase are shown in red. Canonical histone is shown in
blue and histone variants is shown in brown. KMT inhibitors, KDM1 inhibitors, BET inhibitors, HDAC inhibitors are either approved or under
clinical trials. Apart from the targets shown here other possible epigenetic targets for drug development are also available. AC acetylation, ME
methylation, Ub ubiquitination, P phosphorylation

development, chromosome segregation, transcriptional cancer (Khan et al. 2012). It suggests that not only epige-
regulation, DNA repair, and other processes. There are netic modifying enzyme, but also the enzyme for pre-
interesting reports for histone variants macroH2A1 asso- mRNA splicing could be epigenetic therapeutic targets.
ciation with cancer. Reduction of macroH2A1.1 protein is
negatively associated with lung cancer recurrence, and
later reports have shown that alternative splicing of mac- Conclusion
roH2A1 regulates cancer cell proliferation (Sporn et al.
2009; Novikov et al. 2011). There is a growing awareness Involvement of epigenetic factors in cancer development is
that histone modifications and chromatin organization now widely accepted. We have accumulated vast knowl-
influence pre-mRNA splicing and its epigenetic role in edge on how epigenetic aberration can affect cancer

123
Targeting epigenetics for cancer therapy 167

initiation, progression, and metastasis. In this review, we References

have discussed basic epigenetics and its alteration in cancer
as well as available drugs targeting epigenetic mechanisms. Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S,
Karlan BY (2000) BRCA1 promoter region hypermethylation in
Major epigenetic modifications as a cancer target are
ovarian carcinoma: a population-based study. Cancer Res
summarized in Fig. 1. We focused on DNA methylation 60:5329–5333
(Fig. 1a) and histone modification (Fig. 1b) among various Barbano R, Muscarella LA, Pasculli B, Valori VM, Fontana A, Coco
other mechanisms and summarized current studies M, la Torre A, Balsamo T, Poeta ML, Marangi GF, Maiello E,
Castelvetere M, Pellegrini F, Murgo R, Fazio VM, Parrella P
regarding how genetic alteration is linked to abnormal
(2013) Aberrant Keap1 methylation in breast cancer and
epigenetic changes. We should note that each epigenetic association with clinicopathological features. Epigenetics
modification is not a separate or mutually exclusive event, 8:105–112
but rather they are networking with each other to cause Barlési F, Giaccone G, Gallegos-Ruiz MI, Loundou A, Span SW,
Lefesvre P, Kruyt FA, Rodriguez JA (2007) Global histone
subsequent changes. For example, double-strand break
modifications predict prognosis of resected non-small-cell lung
from DNA damage rapidly enhances histone H2A and cancer. J Clin Oncol 25:4358–4364
H2AX phosphorylation. In addition, other histone modifi- Bedford MT, van Helden PD (1987) Hypomethylation of DNA in
cations, such as histone acetylation, and ubiquitination pathological conditions of the human prostate. Cancer Res
47:5274–5276
follow for further recruitment of DNA damage repair
Bos JL (1989) ras oncogenes in human cancer: a review ras
regulatory proteins. oncogenes in human cancer: a review. Cancer Res 49:4682–4689
Along with the accumulation of knowledge about the Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ,
biology and function of epigenetic modifications and their Kouzarides T (1998) Retinoblastoma protein recruits histone
deacetylase to repress transcription. Nature 391:597–601
regulatory mechanisms in cancer, four anti-cancer drugs
Cao J, Yan Q (2012) Histone ubiquitination and deubiquitination in
that target these mechanisms have been currently approved, transcription, DNA damage response, and cancer. Front Oncol
and many others are in clinical trials. However, use of these 2:1–9
drugs have a few limitations. As most of the histone Cecotka A, Polanska J (2018) Region-specific methylation profiling
in acute myeloid leukemia. Interdiscip Sci Comput Life Sci
modifying enzymes have several different substrates, use
10:33–42
of enzyme inhibitors can have limitation in substrate Champagne KS, Kutateladze TG (2009) Structural insight into
specificity. Conversely, targeting non-histone proteins for histone recognition by the ING PHD fingers. Curr Drug Targets
cancer therapy can be another strategy for cancer drug 10:432–441
Chan CH, Fang C, Yarilina A, Prinjha RK, Qiao Y, Ivashkiv LB
development. As cancer results from a series of genetic and
(2015) BET bromodomain inhibition suppresses transcriptional
epigenetic molecular events, overcoming the disease would responses to cytokine-Jak-STAT signaling in a gene-specific
need the use of a combination of multiple genetic and manner in human monocytes. Eur J Immunol 45:287–297
epigenetic targets. To date, the only approved epigenetic Chao C, Chi M, Preciado M, Black MH (2013) Methylation markers
for prostate cancer prognosis: a systematic review. Cancer
anticancer agents are HDAC inhibitors and DNMT inhi-
Causes Control 24:1615–1641
bitors. Our next challenge is to develop additional drugs Chen H, Lorton B, Gupta V, Shechter D (2017) A TGFb-PRMT5-
targeting other classes of epigenetic enzymes and to MEP50 axis regulates cancer cell invasion through histone H3
attempt combinations with those developed to achieve and H4 arginine methylation coupled transcriptional activation
and repression. Oncogene 36:373–386
better substrate and cancer specificity.
Chinnam M, Goodrich DW (2011) RB1, development, and cancer.
Curr Top Dev Biol 94:129–169
Acknowledgements This work was supported by NRF- Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I (2011) TET
2015R1C1A1A01053803 and NRF-2018R1D1A1B07044230. family proteins and their role in stem cell differentiation and
transformation. Cell Stem Cell 9:193–204
Compliance with ethical standards Colón-Bolea P, Crespo P (2014) Lysine methylation in cancer:
SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK
Conflict of interest The authors have no conflicts of interest to pathway. BioEssays 36:1162–1169
disclose. Cooper DN (1983) Eukaryotic DNA methylation. Hum Genet
64:315–333
Open Access This article is distributed under the terms of the Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP
Creative Commons Attribution 4.0 International License (http://crea (2002) Loss of imprinting in colorectal cancer linked to
tivecommons.org/licenses/by/4.0/), which permits unrestricted use, hypomethylation of H19 and IGF2. Cancer Res 62:6442–6446
distribution, and reproduction in any medium, provided you give Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mech-
appropriate credit to the original author(s) and the source, provide a anism to therapy. Cell 150:12–27
link to the Creative Commons license, and indicate if changes were De Koning L, Sauignoni A, Boumendil C, Rehman H, Asselain B,
made. Sastre-Garau X, Almouzni G (2009) Heterochromatin protein la:
a hallmark of cell proliferation relevant to clinical oncology.
EMBO Mol Med 1:178–191

123
168 J. W. Park, J.-W. Han

Denis H, Deplus R, Putmans P, Yamada M, Métivier R, Fuks F (2009) Garcia-Manero G, Rizzieri D, Stock W, Savona MR, Rosenblat
Functional connection between deimination and deacetylation of TL, Berdeja JG, Ravandi F, Rock EP, Hao Y, Azab M, Issa JJ
histones. Mol Cell Biol 29:4982–4993 (2017) Guadecitabine (SGI-110) in treatment-naive patients with
Doerfler W (1983) DNA methylation and gene activity. Annu Rev acute myeloid leukaemia: phase 2 results from a multicentre,
Biochem 52:93–124 randomised, phase 1/2 trial. Lancet Oncol 18:1317–1326
Du Q, Luu P-L, Stirzaker C, Clark SJ (2015) Methyl-CpG-binding Kennedy BK, Liu OW, Dick FA, Dyson N, Harlow E, Vidal M (2001)
domain proteins: readers of the epigenome. Epigenomics Histone deacetylase-dependent transcriptional repression by
7:1051–1073 pRB in yeast occurs independently of interaction through the
Dyson NJ (2016) RB1: a prototype tumor suppressor and an enigma. LXCXE binding cleft. Proc Natl Acad Sci USA 98:8720–8725
Genes Dev 30:1492–1502 Khan DH, Jahan S, Davie JR (2012) Pre-mRNA splicing: role of
Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017) Histone epigenetics and implications in disease. Adv Biol Regul
deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18:1–25 52:377–388
Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins Klughammer J, Kiesel B, Roetzer T, Fortelny N, Nemc A, Nenning
HM, Soria D, Garibaldi JM, Paish CE, Ammar AA, Grainge MJ, KH, Furtner J, Sheffield NC, Datlinger P, Peter N, Nowosielski
Ball GR, Abdelghany MK, Martinez-Pomares L, Heery DM, M, Augustin M, Mischkulnig M, Ströbel T, Alpar D, Ergüner B,
Ellis IO (2009) Global histone modifications in breast cancer Senekowitsch M, Moser P, Freyschlag CF, Kerschbaumer J,
correlate with tumor phenotypes, prognostic factors, and patient Thomé C, Grams AE, Stockhammer G, Kitzwoegerer M,
outcome. Cancer Res 69:3802–3809 Oberndorfer S, Marhold F, Weis S, Trenkler J, Buchroithner J,
Fernández-Medarde A, Santos E (2011) Ras in cancer and develop- Pichler J, Haybaeck J, Krassnig S, Mahdy Ali K, von Campe G,
mental diseases. Genes and Cancer 2:344–358 Payer F, Sherif C, Preiser J, Hauser T, Winkler PA, Kleindienst
Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, W, Würtz F, Brandner-Kokalj T, Stultschnig M, Schweiger S,
Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Dieckmann K, Preusser M, Langs G, Baumann B, Knosp E,
Stratton MR, Futreal PA (2011) COSMIC: mining complete Widhalm G, Marosi C, Hainfellner JA, Woehrer A, Bock C
cancer genomes in the catalogue of somatic mutations in cancer. (2018) The DNA methylation landscape of glioblastoma disease
Nucleic Acids Res 39:945–950 progression shows extensive heterogeneity in time and space.
Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Nat Med 24:1611
Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Knudson AG (1971) Mutation and cancer: statistical study of
Pérez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, retinoblastoma. Proc Natl Acad Sci USA 68:820–823
Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC,
Esteller M (2005) Loss of acetylation at Lys16 and trimethyla- Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, Wigle
tion at Lys20 of histone H4 is a common hallmark of human TJ, Klaus CR, Allain CJ, Raimondi A, Waters NJ, Smith JJ,
cancer. Nat Genet 37:391–400 Porter-Scott M, Chesworth R, Moyer MP, Copeland RA, Richon
Gayatri S, Bedford MT (2014) Readers of histone methylarginine VM, Uenaka T, Pollock RM, Kuntz KW, Yokoi A, Keilhack H
marks. Biochim Biophys Acta 1839:702–710 (2014) Selective inhibition of EZH2 by EPZ-6438 leads to
Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF, potent antitumor activity in EZH2-mutant non-Hodgkin lym-
Daigo Y, Russell P, Wilson A, Sowter HM, Delhanty JD, Ponder phoma. Mol Cancer Ther 13:842–854
BA, Kouzarides T, Caldas C (2000) Mutations truncating the Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of
EP300 acetylase in human cancers. Nat Genet 24:300–303 DNA demethylation. Nature 502:472–479
Georgoulis A, Vorgias CE, Chrousos GP, Rogakou EP (2017) Kriukiene E, Liutkevičiute Z, Klimašauskas S (2012) 5-Hydrox-
Genome instability and cH2AX. Int J Mol Sci 18:1–10 ymethylcytosine—the elusive epigenetic mark in mammalian
Gonzaga C, Lupski JR, Gibbs RA (2012) Human genome sequencing DNA. Chem Soc Rev 41:6916–6930
in health and disease. Annu Rev Med 63:35–61 Li T, Guan J, Huang Z, Hu X, Zheng X (2014) RNF168-mediated
Herold JM, Ingerman LA, Gao C, Frye SV (2011) Drug discovery H2A neddylation antagonizes ubiquitylation of H2A and regu-
toward antagonists of methyl-lysine binding proteins. Curr Chem lates DNA damage repair. J Cell Sci 127:2238–2248
Genomics 5:51–61 Lillico R, Lawrence CK, Lakowski TM (2018) Selective DOT1L,
Heron M, Statistics V (2012) Deaths: leading causes for 2009. Natl LSD1, and HDAC Class i inhibitors reduce HOXA9 expression
Vital Stat Rep 61:1–96 in MLL-AF9 rearranged leukemia cells, but dysregulate the
Heyn H, Esteller M (2012) DNA methylation profiling in the clinic: expression of many histone-modifying enzymes. J Proteome Res
applications and challenges. Nat Rev Genet 13:679–692 17:2657–2667
Hood L, Rowen L (2013) The human genome project: big science Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC, Liaw YF
transforms biology and medicine. Genome Med 5:1 (2001) Genome-wide hypomethylation in hepatocellular car-
Huang M, Zeng S, Zou Y, Shi M, Qiu Q, Xiao Y, Chen G, Yang X, cinogenesis. Cancer Res 61:4238–4243
Liang L, Xu H (2017) The suppression of bromodomain and Liu X, Brenner DA (2016) Liver: DNA methylation controls liver
extra-terminal domain inhibits vascular inflammation by block- fibrogenesis. Nat Rev Gastroenterol Hepatol 13:126–128
ing NF-jB and MAPK activation. Br J Pharmacol 174:101–115 Maes T, Carceller E, Salas J, Ortega A, Buesa C (2015) Advances in
Hudson TJ, Anderson W, Artez A, International Cancer Genome the development of histone lysine demethylase inhibitors. Curr
Consortium (2010) International network of cancer genome Opin Pharmacol 23:52–60
projects. Nature 464:993–998 Marmorstein R, Roth SY (2001) Histone acetyltransferases: function,
Imbach P (2014) Acute lymphoblastic leukemia. Pediatric oncology. structure, and catalysis. Curr Opin Genet Dev 11:155–161
Springer, New York, pp 5–20 Mashimo M, Kato J, Moss J (2013) ADP-ribosyl-acceptor hydrolase 3
Joo HY, Zhai L, Yang C, Nie S, Erdjument-Bromage H, Tempst P, regulates poly (ADP-ribose) degradation and cell death during
Chang C, Wang H (2007) Regulation of cell cycle progression oxidative stress. Proc Natl Acad Sci USA 110:18964–18969
and gene expression by H2A deubiquitination. Nature McLendon R, Friedman A, Bigner D, Cancer Genome Atlas Research
449:1068–1072 Network (2008) Comprehensive genomic characterization
Kantarjian HM, Roboz GJ, Kropf PL, Yee KWL, O’Connell CL, defines human glioblastoma genes and core pathways. Nature
Tibes R, Walsh KJ, Podoltsev NA, Griffiths EA, Jabbour E, 455:1061–1068

123
Targeting epigenetics for cancer therapy 169

Mehta A, Dobersch S, Romero-Olmedo AJ, Barreto G (2015) Padmanabhan B, Mathur S, Manjula R, Tripathi S (2016) Bromod-
Epigenetics in lung cancer diagnosis and therapy. Cancer omain and extra-terminal (BET) family proteins: new therapeu-
Metastasis Rev 34:229–241 tic targets in major diseases. J Biosci 41:295–311
Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Pasque V, Karnik R, Chronis C, Petrella P, Langerman J, Bonora G,
Zhang X, Bernstein BE, Nusbaum C, Jaffe DB, Gnirke A, Song J, Vanheer L, Sadhu Dimashkie A, Meissner A, Plath K
Jaenisch R, Lander ES (2008) Genome-scale DNA methylation (2018) X chromosome dosage influences DNA methylation
maps of pluripotent and differentiated cells. Nature 454:766–770 dynamics during reprogramming to mouse iPSCs. Stem Cell
Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AH, Reports 10:1537–1550
Günther T, Buettner R, Schüle R (2005) LSD1 demethylates Pawlyn C, Bright MD, Buros AF, Stein CK, Walters Z, Aronson LI,
repressive histone marks to promote androgen-receptor- depen- Mirabella F, Jones JR, Kaiser MF, Walker BA, Jackson GH,
dent transcription. Nature 437:436–439 Clarke PA, Bergsagel PL, Workman P, Chesi M, Morgan GJ,
Minsky N, Shema E, Field Y, Schuster M, Segal E, Oren M (2008) Davies FE (2017) Overexpression of EZH2 in multiple myeloma
Monoubiquitinated H2B is associated with the transcribed region is associated with poor prognosis and dysregulation of cell cycle
of highly expressed genes in human cells. Nat Cell Biol control. Blood Cancer J 7:e549-10
10:483–488 Pérez-Salvia M, Esteller M (2017) Bromodomain inhibitors and
Moore KE, Gozani O (2014) An unexpected journey: lysine cancer therapy: from structures to applications. Epigenetics
methylation across the proteome. Biochim Biophys Acta 12:323–339
1839:1395–1403 Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray
Moreno DA, Scrideli CA, Cortez MA, de Paula Queiroz R, Valera SJ, Greenman CD, Varela I, Lin ML, Ordóñez GR, Bignell GR,
ET, da Silva Silveira V, Yunes JA, Brandalise SR, Tone LG Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L,
(2010) Differential expression of HDAC3, HDAC7 and HDAC9 Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock
is associated with prognosis and survival in childhood acute RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z,
lymphoblastic leukaemia: research paper. Br J Haematol Leroy C, Marshall J, Menzies A, Mudie LJ, Ning Z, Royce T,
150:665–673 Schulz-Trieglaff OB, Spiridou A, Stebbings LA, Szajkowski L,
Nakajima H, Kunimoto H (2014) TET2 as an epigenetic master Teague J, Williamson D, Chin L, Ross MT, Campbell PJ,
regulator for normal and malignant hematopoiesis. Cancer Sci Bentley DR, Futreal PA, Stratton MR (2010) A comprehensive
105:1093–1099 catalogue of somatic mutations from a human cancer genome.
Nevins JR (2001) The Rb/E2F pathway and cancer. Hum Mol Genet Nature 463:191–196
10:699–703 Prenzel T, Begus-Nahrmann Y, Kramer F, Hennion M, Hsu C,
Nguyen AT, Zhang Y (2011) The diverse functions of Dot1 and Gorsler T, Hintermair C, Eick D, Kremmer E, Simons M,
H3K79 methylation. Genes Dev 3:1345–1358 Beissbarth T, Johnsen SA (2011) Estrogen-dependent gene
Nienstedt JC, Schroeder C, Clauditz T, Simon R, Sauter G, transcription in human breast cancer cells relies upon protea-
Muenscher A, Blessmann M, Hanken H, Pflug C (2018) EZH2 some-dependent monoubiquitination of histone H2B. Cancer Res
overexpression in head and neck cancer is related to lymph node 71:5739–5753
metastasis. J Oral Pathol Med 47:240–245 Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of ras
Norwood LE, Moss TJ, Margaryan NV, Cook SL, Wright L, Seftor mutations in cancer. Cancer Res 72:2457–2467
EA, Hendrix MJ, Kirschmann DA, Wallrath LL (2006) A Qian C, Zhou M (2006) SET domain protein lysine methyltrans-
requirement for dimerization of HP1Hsain suppression of breast ferases: Structure, specificity and catalysis. Cell Mol Sci
cancer invasion. J Biol Chem 281:18668–18676 63:2755–2763
Novikov L, Park JW, Chen H, Klerman H, Jalloh AS, Gamble MJ Raj K, Mufti GJ (2006) Azacytidine (VidazaÒ) in the treatment of
(2011) QKI-mediated alternative splicing of the histone variant myelodysplastic syndromes. Ther Clin Risk Manag 2:377–388
MacroH2A1 regulates cancer cell proliferation. Mol Cell Biol Rideout WM, Coetzee GA, Olumi AF, Spruck CH, Jones PA (1991)
31:4244–4255 5-Methylcytosine as an endogenous mutagen in the p53 tumor
Nowak SJ, Corces VG (2004) Phosphorylation of histone H3: a suppressor gene. Science 22:207–219
balancing act between chromosome condensation and transcrip- Rowley JD (2001) Chromosome translocations: dangerous liaisons
tional activation. Trends Genet 20:214–220 revisited. Nat Rev Cancer 1:245–250
Nowell PC (2007) Review series personal perspective Discovery of Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP
the Philadelphia chromosome: a personal perspective. J Clin (1991) Allele-specific hypermethylation of the retinoblastoma
Invest 117:2033–2035 tumor-suppressor gene. Am J Hum Genet 48:880–888
Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, Santos FPS, Kantarjian H, Garcia-Manero G, Issa JP, Ravandi F
Mohammad HP, Chen W, Daniel VC, Yu W, Berman DM, (2010) Decitabine in the treatment of myelodysplastic syn-
Jenuwein T, Pruitt K, Sharkis SJ, Watkins DN, Herman JG, dromes. Expert Rev Anticancer Ther 10:9–22
Baylin SB (2007) A stem cell-like chromatin pattern may Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, Wang
predispose tumor suppressor genes to DNA hypermethylation Q, Chia D, Goodglick L, Kurdistani SK (2009) Global levels of
and heritable silencing. Nat Genet 39:237–242 histone modifications predict prognosis in different cancers. Am
Okano M, Xie S, Li E (1998) Cloning and characterization of a family J Pathol 174:1619–1628
of novel mammalian DNA (cytosine-5) methyltransferases Non- Shiio Y, Eisenman RN (2003) Histone sumoylation is associated with
invasive sexing of preimplantation stage mammalian embryos. transcriptional repression. Proc Natl Acad Sci USA
Nat Am 19:219–220 100:13225–13230
Ota T, Suto S, Katayama H, Han ZB, Suzuki F, Maeda M, Tanino M, Skakkebæk A, Nielsen MM, Trolle C, Vang S, Hornshøj H,
Terada Y, Tatsuka M (2002) Increased mitotic phosphorylation Hedegaard J, Wallentin M, Bojesen A, Hertz JM, Fedder J,
of histone H3 attributable to AIM-1/aurora-B overexpression Østergaard JR, Pedersen JS, Gravholt CH (2018) DNA hyper-
contributes to chromosome number instability. Cancer Res methylation and differential gene expression associated with
62:5168–5177 Klinefelter syndrome. Sci Rep 8:13740

123
170 J. W. Park, J.-W. Han

Spange S, Wagner T, Heinzel T, Krämer OH (2009) Acetylation of (2010) Quantitative interaction proteomics and genome-wide
non-histone proteins modulates cellular signalling at multiple profiling of epigenetic histone marks and their readers. Cell
levels. Int J Biochem Cell Biol 41:185–198 142:967–980
Spencer DH, Russler-Germain DA, Ketkar S, Helton NM, Lamprecht Vogelstein B, Papadopoulos N, Velculescu V, Zhou S, Diaz LA Jr,
TL, Fulton RS, Fronick CC, O’Laughlin M, Heath SE, Shinawi Kinzler KW (2013) Cancer genome landscapes. Science
M, Westervelt P, Payton JE, Wartman LD, Welch JS, Wilson 339(6127):1546–1558
RK, Walter MJ, Link DC, DiPersio JF, Ley TJ (2017) CpG Wasenius VM, Hemmer S, Kettunen E, Knuutila S, Franssila K,
Island hypermethylation mediated by DNMT3A is a conse- Joensuu H (2003) Hepatocyte growth factor receptor, matrix
quence of AML progression. Cell 168:801–816.e13 metalloproteinase-11, tissue inhibitor of metalloproteinase-1,
Sporn JC, Kustatscher G, Hothorn T, Collado M, Serrano M, Muley and fibronectin are up-regulated in papillary thyroid carcinoma:
T, Schnabel P, Ladurner AG (2009) Histone macroH2A isoforms a cDNA and tissue microarray study. Clin Cancer Res 9:68–75
predict the risk of lung cancer recurrence. Oncogene Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B,
28:3423–3428 Nielsen ML, Schmitz C, Butler DS, Yates JR 3rd, Delahunty
Sprüssel A, Schulte JH, Weber S, Necke M, Händschke K, Thor T, CM, Hahn P, Lengeling A, Mann M, Proudfoot NJ, Schofield CJ,
Pajtler KW, Schramm A, König K, Diehl L, Mestdagh P, Böttger A (2009) Jmjd6 catalyses lysyl-hydroxylation of
Vandesompele J, Speleman F, Jastrow H, Heukamp LC, Schüle U2AF65, a protein associated with RNA splicing. Science
R, Dührsen U, Buettner R, Eggert A, Göthert JR (2012) Lysine- 325:90–94
specific demethylase 1 restricts hematopoietic progenitor prolif- Wei H, Mundade R, Lange KC, Lu T (2014) Protein arginine
eration and is essential for terminal differentiation. Leukemia methylation of non-histone proteins and its role in diseases. Cell
26:2039–2051 Cycle 13:32–41
Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Xu Y, Vakoc CR (2017) Targeting cancer cells with BET bromod-
Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, omain inhibitors. Cold Spring Harb Perspect Med 7:1–17
Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Yang XJ (2004) The diverse superfamily of lysine acetyltransferases
Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, and their roles in leukemia and other diseases. Nucleic Acids Res
Löwenberg B, Tallman MS (2018) The DOT1L inhibitor 32:959–976
pinometostat reduces H3K79 methylation and has modest Yang Y, Bedford MT (2013) Protein arginine methyltransferases and
clinical activity in adult acute leukemia. Blood 131:2662–2669 cancer. Nat Rev Cancer 13:37–50
Sun W, Liu Y, Glazer CA, Shao C, Bhan S, Demokan S, Zhao M, Yoshimatsu M, Toyokawa G, Hayami S, Unoki M, Tsunoda T, Field
Rudek MA, Ha PK, Califano JA (2010) TKTL1 is activated by HI, Kelly JD, Neal DE, Maehara Y, Ponder BA, Nakamura Y,
promoter hypomethylation and contributes to head and neck Hamamoto R (2011) Dysregulation of PRMT1 and PRMT6,
squamous cell carcinoma carcinogenesis through increased Type I arginine methyltransferases, is involved in various types
aerobic glycolysis and HIF1a stabilization. Clin Cancer Res of human cancers. Int J Cancer 128:562–573
16:857–866 Zhang C, Zhong JF, Stucky A, Chen XL, Press MF, Zhang X (2015)
Swatek KN, Komander D (2016) Ubiquitin modifications. Cell Res Histone acetylation: novel target for the treatment of acute
26:399–422 lymphoblastic leukemia. Clin Epigenetics 7:1–10
Tanaka S, Arii S, Yasen M, Mogushi K, Su NT, Zhao C, Imoto I, Zhou W, Zhu P, Wang J, Pascual G, Ohgi KA, Lozach J, Glass CK,
Eishi Y, Inazawa J, Miki Y, Tanaka H (2008) Aurora kinase B is Rosenfeld MG (2008) Histone H2A monoubiquitination
a predictive factor for the aggressive recurrence of hepatocellular represses transcription by inhibiting RNA polymerase II tran-
carcinoma after curative hepatectomy. Br J Surg 95:611–619 scriptional elongation. Mol Cell 29:69–80
Tao YF, Li P, Du XJ, Sun LC, Hu SY, Lu J, Cao L, Zhao WL, Feng Zhu P, Zhou W, Wang J, Puc J, Ohgi KA, Erdjument-Bromage H,
X, Wang J, Wu D, Wang N, Ni J, Pan J (2013) Differential Tempst P, Glass CK, Rosenfeld MG (2007) A histone H2A
mRNA expression levels of human histone-modifying enzymes deubiquitinase complex coordinating histone acetylation and H1
in normal karyotype B cell pediatric acute lymphoblastic dissociation in transcriptional regulation. Mol Cell 27:609–621
leukemia. Int J Mol Sci 14:3376–3394 Zhu K, Liu Q, Zhou Y, Tao C, Zhao Z, Sun J, Xu H (2015)
Turinetto V, Giachino C (2015) Survey and summary multiple facets Oncogenes and tumor suppressor genes: comparative genomics
of histone variant H2AX: a DNA double-strand-break marker and network perspectives. BMC Genomics 16:S8
with several biological functions. Nucleic Acids Res Zou L, Zhang H, Du C, Liu X, Zhu S, Zhang W, Li Z, Gao C, Zhao X,
43:2489–2498 Mei M, Bao S, Zheng H (2012) Correlation of SRSF1 and
Uckelmann M, Sixma TK (2017) Histone ubiquitination in the DNA PRMT1 expression with clinical status of pediatric acute
damage response. DNA Repair (Amst) 56:92–101 lymphoblastic leukemia. J Hematol Oncol 5:1–11
Varier RA, Timmers HTM (2011) Histone lysine methylation and
demethylation pathways in cancer. Biochim Biophys Act
1815:75–89 Publisher’s Note
Vera E, Canela A, Fraga MF, Esteller M, Blasco MA (2008)
Epigenetic regulation of telomeres in human cancer. Oncogene Springer Nature remains neutral with regard to jurisdictional claims in
27:6817–6833 published maps and institutional affiliations.
Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, Butter F,
Lee KK, Olsen JV, Hyman AA, Stunnenberg HG, Mann M

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