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Abstract | Several protein lysine methyltransferases and demethylases have been identified
to have critical roles in histone modification. A large body of evidence has indicated that
their dysregulation is involved in the development and progression of various diseases,
including cancer, and these enzymes are now considered to be potential therapeutic targets.
Although most studies have focused on histone methylation, many reports have revealed
that these enzymes also regulate the methylation dynamics of non-histone proteins such as
p53, RB1 and STAT3 (signal transducer and activator of transcription 3), which have
important roles in human tumorigenesis. In this Review, we summarize the molecular
functions of protein lysine methylation and its involvement in human cancer, with a particular
focus on lysine methylation of non-histone proteins.
Sadenosyl-lmethionine
(AdoMet). A molecule
synthesized from methionine
and ATP by methionine adeno
syltransferase. The methylation
group attached to the
methionine sulphur atom in
AdoMet is chemically reactive.
This allows donation of this
group to an acceptor substrate
in transmethylation reactions.
Section of Hematology/
Oncology, Department of
Medicine, The University of
Chicago, 5841S.Maryland
Avenue, MC 2115 Chicago,
Illinois 60637, USA.
Correspondence to R.H.
e-mail: rhamamoto@
medicine.bsd.uchicago.edu
doi:10.1038/nrc3884
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2015 Macmillan Publishers Limited. All rights reserved
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regulation of gene expression but also in the regulation of
cellular signal transduction pathways. Furthermore, dys
regulation of non-histone lysine methylation seems to be
involved in the development and progression of cancer.
As anticancer drugs targeting PKMTs and PKDMs have
actively been developed in recent years, it is essential to
clarify the substrates of these enzymes to correctly under
stand the mechanism of action of thesedrugs.
Monoamine oxidase
A family of enzymes that
catalyse the oxidation of
monoamines. They belong to
the protein family of
flavin-containing amine
oxidoreductases.
a Lysine methylation
PKMT
H H
H N+
PKMT
H3C H
H N+
AdoMet AdoHcy
AdoMet AdoHcy
O
+H
3N
AdoMet
+H
Lysine
H3C CH3
H3C N+
AdoHcy
3N
PKMT
H3C CH3
H N+
+H
3N
+H
Dimethyl lysine
Monomethyl lysine
3N
Trimethyl lysine
LSD1
FAD
H2O2
H2C
CH3
N+
FADH2
+H
3N
H2C=O
Formaldehyde
H3C H
H N+
O2
Dimethyl lysine
H2O
OH
H2C CH3
H N+
+H
3N
+H
3N
Imine intermediate
+H
3N
Monomethyl lysine
JKDM
Fe(II)
-ketoglutarate Succinate
+ O2
+ CO2
OH
H2C CH3
H N+
O
+H
3N
Dimethyl lysine
H2C=O
Formaldehyde
H CH3
H N+
O
+H
3N
O
+H
3N
Monomethyl lysine
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a Other protein modications
Competitive
inhibition
K Me
Indirect eect K Me
on other
modications
Ub
Ac
P S
b Proteinprotein interactions
Methylatedlysine-specic
binding proteins
localization
Me Me Nucleus
HSP70 AURKB
Activate
Chromodomain
Me
Me
K
Inhibition of
proteinprotein
interactions
d Subcellular
c Protein stability
HSP70
Me
Ub Ub
Ub Ub Ub
Inhibition of
Me
Me
K
polyubiquitylation
Protein degradation
by proteasomes
Me
Ub
Ub
Ub Ub
Ub
e Promoter binding
Me
HSP70
Transcription
factors
Methylation
activates
transcription
Promoter
Cytoplasm
Figure 2 | Molecular functions of lysine methylation in human tumorigenesis. The biological Nature
importance
of lysine
Reviews
| Cancer
methylation is primarily categorized into five groups. a | Lysine methylation affects other protein modifications directly
(through competitive inhibition) or indirectly. b | Lysine methylation regulates proteinprotein interactions. Methylatedlysine-specific binding proteins have been reported, and these proteins contain motifs that specifically recognize
methylated lysine residues such as chromodomains and Tudor domains. Methylated lysine can also negatively regulate
some proteinprotein interactions. c | Lysine methylation competitively inhibits the polyubiquitylation of lysine residues
and stabilizes the protein. Additionally, lysine methylation also promotes the polyubiquitylation of other lysine residues on
the same protein, leading to protein destabilization. d | Subcellular localization is regulated by lysine methylation. For
example, methylated heat shock protein 70 (HSP70) proteins are predominantly localized in the nucleus, whereas
unmodified versions are predominantly localized in the cytoplasm. e | Lysine methylation regulates promoter binding
affinity of transcription factors, thereby changing transcription levels of target genes. Ac, acetyl group; AURKB, Aurora
kinase B; P, phosphate group; Me, methyl group; Ub, ubiquitin.
Oxygenase
An enzyme of the
oxidoreductase class that
catalyses the incorporation of
both atoms of molecular
oxygen into the substrate.
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contacts42. This result reveals that increased hydropho
bicity of lysine residues by methylation can enhance
the promoter binding ability of transcription factors.
Tudor domains
Protein domains originally
identified as a region of 50
amino acids found in the
Drosophila melanogaster
Tudor protein. The structurally
characterized Tudor domain in
human proteins recognizes
symmetrically dimethylated
arginine. This domain is also
reported as a methyl
lysine-binding protein module.
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Table 1 | Protein lysine methyltransferases and demethylases involved in human tumorigenesis and their substrates
Family
Enzyme
name (alias)
Domain
Subcellular Substrate
localization
Histone
Cancer type
Refs
Non-histone
Lysine methyltransferases
Polycomb
complex
EZH2 (KMT6)
Nucleus*
and
cytoplasm
H3K27 and
H2BK120
17,31,37,74
SMYD
family
SMYD2
(KMT3C)
SET
Cytoplasm*
and nucleus
H3K4 and
H3K36
22,25,27,44,
51,52,69,
111113
SMYD3
(KMT3E)
SET
Cytoplasm*
and nucleus
H3K4 and
H4K5
VEGFR1 and
MAP3K2
SET, PWWP,
AWS, PHD,
RING and
PostSET
Nucleus*
H3K36
and
chromosome
NFB
122124
WHSC1
(MMSET and
NSD2)
SET, PWWP,
AWS, PHD,
RING and
PostSET
Nucleus*,
H3K36
cytoplasm
and
chromosome
125129
WHSC1L1
(NSD3)
SET, PWWP,
AWS, PHD,
RING and
PostSET
Nucleus*
H3K36
and
chromosome
130132
SETD1A
(KMT2F)
Nucleus*
H3K4
and
chromosome
HSP70
23,133
SETD7
(KMT7)
Nucleus*
H3K4
and
chromosome
PPP1R12A, p53,
NFB, E2F1, DNMT1
and STAT3
24,39,55,66,
73,134,135
SETD8
(KMT5A)
SET
Nucleus*
H4K20
and
chromosome
47,75
SUV39
family
SUV39H2
(KMT1B)
SET, PreSET,
PostSET and
chromodomain
Nucleus*
H3K9 and
and
H2AXK134
chromosome
32,136
EHMT
family
EHMT2
(KMT1C)
SET, PreSET,
PostSET and
ANK
Nucleus*
H3K9
and
chromosome
C/EBP
19,71,
137,138
MLL family
MLL2
(KMT2D)
Nucleus*
H3K4
139
MLL3
(KMT2C)
Nucleus*
H3K4
140142
DOT1L
(KMT4)
AT_hook
Nucleus*
H3K79
MLL
143145
SETD
family
DOT1L
family
4,13,26,33,
114121
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Table 1 (cont.) | Protein lysine methyltransferases and demethylases that are involved in human tumorigenesis and their substrates
Family
Enzyme
Domain
name (alias)
Subcellular Substrate
localization
Histone
Cancer type
Refs
Non-histone
Lysine demethylases
LSD1
family
LSD1
(KDM1A)
FAD-binding2
and SWIRM
Nucleus*
H3K4 and
H3K9
PPP1R12A, p53, ER
and STAT3
11,24,45,46
JMJD
family
JMJD1A
(KDM3A)
JmjC
Nucleus*
and
cytoplasm
H3K9
20,146,147
JMJD2A
(KDM4A)
Nucleus*
H3K9 and
H3K36
JMJD2B
(KDM4B)
Nucleus*
H3K9
JMJD3
(KDM6B)
JmjC
Nucleus*
H3K27
Glioblastoma
UTX
UTX
(KDM6A)
Nucleus*
H3K27
156159
JARID
family
JARID1B
(KDM5B)
JmjC, JmjN,
ARID, PHD,
ZFC5HC2 and
PLU1
Nucleus*
H3K4
160164
148151
21,152154
155
ACC, adenocarcinoma; AML, acute myeloid leukaemia; CCC, cholangiocarcinoma; C/EBP, CCAAT/enhancer binding protein-; CML, chronic myelogenous
leukaemia; CRC, colorectal cancer; DNMT1, DNA (cytosine5-)-methyltransferase 1; DOT1L, DOT1like histone H3K79 methyltransferase; EHMT, euchromatic
histone-lysine Nmethyltransferase; ER, oestrogen receptor-; H3K27, histone H3 lysine 27; HCC, hepatocellular carcinoma; HSP, heat shock protein; JARID,
Jumonji, AT-rich interactive domain; JMJD, Jumonji domain-containing; KMT, lysine N-methyltransferase; LSD1, lysine-specific demethylase 1; MAP3K2, MAPK
kinase kinase 2; MLL, mixed-lineage leukaemia; MTC, medullary thyroid cancer; NF-B, nuclear factor-B; NSCLC, non-small cell lung carcinoma; NSD, nuclear
receptor-binding SET domain-containing; PARP1, poly(ADP-ribose) polymerase 1; PCNA, proliferating cell nuclear antigen; PPP1R12A, protein phosphatase 1,
regulatory subunit 12A; RCC, renal cell carcinoma; ROR, retinoic acid-related orphan nuclear receptor; SCLC, small cell lung carcinoma; SETD, SET
domain-containing; SMYD, SET and MYND-domain-containing; STAT3, signal transducer and activator of transcription 3; STT, soft tissue tumour; SUV39H,
suppressor of variegation 39 homologue; TALL, Tcell acute lymphoblastic leukaemia; VEGFR1, vascular endothelial growth factor receptor 1.*The predominant
subcellular localization.
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a
53BP1
Me Me
p53
p53 inactivation
K370me2 to
K370me1
K370me1
SMYD2
LSD1
53BP1
LSD1
p53
Me
Inhibition of K370me1
p53 inactivation
K372me1
K382me1
SETD7
SETD8
Me Me
Me
PRR
DBDL
OD
CTD
ANK
PPP1R12A
CC
K442 Stabilizes PPP1R12A protein
Me
CDK4
SETD7
LSD1
High anity
PPP1R12A
dephosphorylates
RB1
SMYD2
Me
Enhances RB1
K810 hyperphosphorylation
RB1
Pocket A
Pocket B
SETD7
LSD1
CTD
SMYD2-dependent RB1
methylation activates E2F
Me
K185
E2F1
DBD
CC
MB
TD
Regulation of E2F1-dependent
apoptosis in p53-decient cancer cells
c
VEGFR1
TK1
TM
IG-LD
K260me2
or K260me3
K831me2
SMYD3
Me
K831
Me
Inhibition of
PP2A interaction
TK2
Activation of
kinase activity
PP2A
K260
MAP3K2
PB1
Activation of oncogenic
RAS signalling
Kinase domain
Nature Reviews | Cancer
Figure 3 | Effects of lysine methylation on the pathways of p53, RB1 and protein kinases. a | Methylation of lysine
at residues 370, 372 and 382 in the carboxyterminal domain (CTD) of p53 has been identified. Lysine 370-dimethylated p53
(p53K370me2) can promote the association of p53 with the co-activator p53binding protein1 (53BP1) through tandem
Tudor domains in 53BP1. By contrast, lysine-specific demethylase 1 (LSD1) prevents the accumulation of p53K370me2 by
demethylating this site, thereby preventing the binding of 53BP1 to p53. Both LSD1 and the protein lysine
methyltransferase (PKMT) SET and MYND-domain containing 2 (SMYD2) produce p53K370me1 that results in the
inactivation of p53. Meanwhile, the PKMT SETD7 monomethylates K372 (K372me1), which inhibits K370me1 and activates
p53. SETD8 also inactivates p53 through monomethylation of K382 (K382me1). b | The RB1 pathway is regulated by lysine
methylation. Lysine methylation sites on RB1, E2F1 and protein phosphatase 1, regulatory subunit 12A (PPP1R12A) are
displayed. SETD7 monomethylates K442, which stabilizes PPP1R12A, and this methylation is reversibly demethylated by
LSD1. SMYD2 monomethylates K810 on RB1 and increases the affinity between cyclin-dependent kinase 4 (CDK4) and RB1,
which enhances hyperphosphorylation of RB1 and therefore activates E2F. SETD7 monomethylates K185 of E2F1
(E2F1K185me1), which prevents apoptotic functions of E2F1 in p53deficient cells during DNA damage, and E2F1K185me1
is demethylated by LSD1, promoting E2F1 stability and apoptosis. c | K831 of vascular endothelial growth factor receptor1
(VEGFR1) and K260 of MAPK kinase kinase 2 (MAP3K2) are methylated by SMYD3. VEGFR1K831 dimethylation by SMYD3
activates the kinase activity of VEGFR1. K260 of MAP3K2 is dimethylated and trimethylated by SMYD3, which activates
oncogenic RAS signalling through inhibition of the MAP3K2PP2A (protein phosphatase 2A) interaction. ANK, ankyrin
repeat; CC, coiled-coil domain; DBD, DNA-binding domain; IG-LD, immunoglobulin-like domain; MB, marked-box;
OD,oligomerization domain; PB1, Phox and Bem1p; PRR, proline-rich region; TA, transcription-activation domain;
TD,transactivation domain; TK, tyrosine kinase domain; TM, transmembrane domain.
116 | FEBRUARY 2015 | VOLUME 15
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Nitrosylation
Nitrosylation, specifically
Snitrosylation, involves the
covalent incorporation of a
nitric oxide moiety into thiol
groups, to form Snitrosothiol.
Snitrosylation is a
physiologically important
post-translational modification
that affects a variety of
proteins involved in a number
of cellular processes.
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a
Me
K37
Gene activation
in response to
TNF stimulation
PP2A
Me
Me
K221
Me
PHF20
TA2
ER
TA1
K310
Me Suppression of NF-Bregulated genes through
High
EHMT1-dependent
anity
H3K9 methylation
DBD Hinge
STAT3
DBD LZ
II
NTD
Me
SETD7
EHMT2
Agonistantagonist
distinction
Promotes STAT3
activity in GSCs
CC
K140
Represses
transcriptional
activity
Me
Ligand-binding
K180me3
EZH2
EHMT1
Me
K180
K39
Ac
Transcriptional
activity
TAs
I
Prevents ER target
gene activation under
an oestrogendepleted condition
p300
K266 K268
IPT_NF-B
Constitutive
activation of
NF-B activity
C/EBP
LSD1
SMYD2
K218 K221
RHD-n
RELA
b K266me1; K266me2
K310me1
SETD6
DBD
LD
SH2
CTD
Negatively regulates
transcription of
some specic genes
LSD1
K140me2
e
PCNA
f
PCNA_N
PARP1
PCNA_C
K248
Me
Interaction
Automodication domain
DBD
Stabilizes
PCNA protein
NLS
Catalytic domain
K528
Me
High anity
SETD8
K248me1
FEN1
Enhances poly(ADP-ribose)
formation after oxidative stress
SMYD2
K528me1
Figure 4 | Effects of lysine methylation on transcription factors and nuclear proteins. a | Lysine 37 of RELA, a subunit
Nature Reviews | Cancer
of nuclear factor-B (NFB) , is monomethylated by SETD7, which activates NFB-dependent genes in response to
tumour necrosis factor (TNF) stimulation. Nuclear receptor-binding SET domain-containing protein 1 (NSD1)
monomethylates K218 (K218me1) and dimethylates K221 (K221me2), resulting in constitutive NFB activation through
interaction with PHF20, which disrupts the recruitment of PP2A to RELA, and these sites are reversibly demethylated by
Fbox and leucine-rich repeat protein 11 (FBXL11). SETD6 monomethylates K310 of RELA and suppresses
NFB-regulated genes through euchromatic histone-lysine Nmethyltransferase1 (EHMT1)dependent H3K9
methylation. b | SMYD2mediated oestrogen receptor (ER) methylation prevents ER target gene activation under an
oestrogen-depleted condition, and lysine-specific demethylase 1 (LSD1) demethylates this site. c | K39 of CCAAT/
enhancer-binding protein- (C/EBP) is methylated by EHMT2, which represses C/EBP transcriptional activity. d | K140 of
signal transducer and activator of transcription 3 (STAT3) is dimethylated by SETD7, which negatively regulates the
transcription of various STAT3 target genes. STAT3K140me2 is reversibly demethylated by LSD1. EZH2 trimethylates K180
of STAT3, which promotes STAT3 activity in glioblastoma stem-like cells (GSCs). e | SETD8 monomethylates K248 of
proliferating cell nuclear antigen (PCNA), and this methylation stabilizes the PCNA protein and enhances the interaction
between PCNA and flap endonuclease 1 (FEN1). f | SMYD2 monomethylates K528 of poly(ADP-ribose) polymerase1
(PARP1) and enhances poly(ADP-ribose) formation after oxidative stress. CC, coiled-coil domain; CTD, carboxy-terminal
domain; DBD, DNA-binding domain; IPT, immunoglobulin-plexin-transcription; LD, linker domain; LZ, leucine zipper
domain; NLS, nuclear localization signal; NTD, amino terminal domain; PCNA_C, PCNA C-terminal domain; PCNA_N,
PCNA N-terminal domain; PHF20, PHD finger protein 20; RHD, REL homology domain; SH2, Src homology 2 domain;
TA,transcription-activation domain; Y, conserved tyrosine domain.
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Okazaki fragments
Short, newly synthesized DNA
fragments that are formed on
the lagging template strand
during DNA replication. The
fragments are produced
because of the need for DNA
polymerase to always
synthesize in a 5-to-3
direction and are subsequently
ligated together to form a
continuous strand.
REVIEWS
Table 2 | Selected inhibitors targeting protein lysine methyltransferases and demethylases
Inhibitor
name
Chemical structure
BIX01294
HN
H3C
Target
enzyme
IC50 value
(enzyme)
Cancer type
Phase
EHMT2
0.18M
None
Preclinical
EHMT2
<15nM
None
Preclinical
SMYD2
0.12M
None
Preclinical
EZH2
0.5nM (Ki)
DLBCL
Preclinical
EZH2
24nM (Ki)
Non-Hodgkin
lymphoma
Preclinical
EZH2
11nM
(Ki=2.5nM)
Non-Hodgkin
lymphoma
PhaseI/II
DOT1L
80pM (Ki)
Relapsed/refractory
AML, ALL or MLL
with rearrangement
of the MLL gene,
including 11q23
or partial tandem
duplication
PhaseI
N
N
O
CH3
O CH3
UNC0638
HN
N
CH3
N
O
N
AZ505
HO
Cl
H
N
N
H
Cl
O
HN
O
GSK126
O
NH
NH
O
HN
EPZ005687
N N
H
N
HN
H
N
EPZ6438
N
O
O
H
N
H2N
HO
OH
N
O
H
N
OR
EPZ5676
H2N
N
N
N
N
NH
HO
OH
GSK2879552
Not available
LSD1
Not available
Relapsed/refractory
SCLC
PhaseI
ORY1001
Not available
LSD1
Not available
AML
PhaseI/IIA
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; DLBCL, diffuse large B cell lymphoma; DOT1L, DOT1like histone H3K79 methyltransferase;
IC50, half-maximal inhibitory concentration; Ki, inhibition constant; LSD1, lysine-specific demethylase 1; MLL, mixed-lineage leukaemia; SCLC, small cell lung
cancer; SMYD2, SET and MYND domain-containing 2.
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effectively inhibits the proliferation of EZH2mutant
DLBCL cell lines and xenografts in mice15. The other is
EPZ005687, which also targets Y641- and A677mutated
EZH2 found in non-Hodgkin lymphoma97 (TABLE2).
Recently, a new inhibitor (EPZ6438) specific for mutated
EZH2 has been reported that has superior potency and
properties to EPZ005687, including better oral bioavail
ability 98 (TABLE2). A PhaseI/II clinical trial of EPZ6438
has begun for patients with non-Hodgkin lymphoma.
By contrast, 10% of patients with myelodysplastic syn
drome (MDS) harbour lossoffunction mutations in
EZH2 (REF.99), and EZH2 mutations in these patients are
associated with significantly worse prognosis, although
this is not due to transformation to acute myeloid leu
kaemia 100. Patients with MDS without monosomy
7/del(7q) chromosome anomalies also have reduced
expression of EZH2 in CD34+ cells101, which implies the
possibility that EZH2 functions as a tumour suppressor
in MDS, and similar results are also reported in myelo
proliferative neoplasm102. Along this line, patients with
colorectal cancer who have EZH2 overexpression have a
good prognosis17. These results highlight that although
there is no doubt that it is an ideal therapeutic target,
caution is necessary in developing anticancer therapies
targetingEZH2.
EPZ5676, a potent and selective aminonucleoside
inhibitor of the PKMT DOT1L 103,104, has also been
studied in a PhaseI clinical trial for the treatment of
patients with acute leukaemia in which the MLL gene
has undergone rearrangement or tandem duplication
(TABLE2). The data derived from these clinical studies
are expected to provide important information regard
ing further possibilities and potential issues in the
development of anticancer drugs targetingPKMTs.
With regard to PKDMs as candidates for anticancer
therapy development, inhibitors targeting LSD1 have
been actively studied. LSD1 is significantly overexpressed
in human cancer, including small cell lung carcinoma,
and has a crucial role in the growth of cancer cells
through the regulation of chromatin functions46. Because
of the similarity in the catalytic and structural proper
ties, drugs targeting monoamine oxidase (MAO) were
first investigated as LSD1 inhibitors. For example, tranyl
cypromine, an MAO inhibitor used as an antidepressant
drug, can inhibit LSD1 (REF.105), and tranylcypromine
or its analogues show antitumour activity when admin
istered alone or in combination with all-trans-retinoic
acid in leukaemia models106. Given that anti-MAO drugs
are not specific to LSD1 and induce substantial toxicity
invivo, further refined LSD1specific inhibitors have
recently been developed107. In particular, a PhaseI clini
cal trial of GSK2879552, an LSD1specific inhibitor, has
been initiated for patients with relapsed/refractory small
cell lung cancer (TABLE2). Additionally, a PhaseI clinical
trial of the novel LSD1 inhibitor ORY1001 has begun for
acute myeloid leukaemia (TABLE2).
As mentioned above, in addition to the LSD1 fam
ily proteins, JmjC-containing proteins also have PKDM
activity. In 2012, Kruidenier etal.108 reported a selective
JmjC H3K27 demethylase inhibitor. The authors indicated
the relevance and tractability of demethylase inhibition
REVIEWS
Ambler,R.P. & Rees,M.W. -Nmethyl-lysine in
bacterial flagellar protein. Nature 184, 5657 (1959).
2. Murray,K. The occurrence of -Nmethyl lysine in
histones. Biochemistry 3, 1015 (1964).
3. Clarke,S.G. & Tamanoi,F. (eds) The Enzymes: Protein
Methyltransferases Vol. 24 (Academic Press, 2006).
4. Hamamoto,R. etal. SMYD3 encodes a histone
methyltransferase involved in the proliferation of
cancer cells. Nature Cell Biol. 6, 731740 (2004).
This is the pioneering report to describe that
dysregulation of a PKMT can cause tumorigenesis.
5. Rea,S. etal. Regulation of chromatin structure by
site-specific histone H3 methyltransferases. Nature
406, 593599 (2000).
This is the first report to show the existence of a
PKMT.
6. Tachibana,M., Sugimoto,K., Fukushima,T. &
Shinkai,Y. SET domain-containing protein, G9a, is a
novel lysine-preferring mammalian histone
methyltransferase with hyperactivity and specific
selectivity to lysines 9 and 27 of histone H3. J.Biol.
Chem. 276, 2530925317 (2001).
7. Schlichter,A. & Cairns,B.R. Histone trimethylation by
Set1 is coordinated by the RRM, autoinhibitory, and
catalytic domains. EMBO J. 24, 12221231 (2005).
8. Ringrose,L., Ehret,H. & Paro,R. Distinct
contributions of histone H3 lysine 9 and 27
methylation to locus-specific stability of polycomb
complexes. Mol. Cell 16, 641653 (2004).
9. Feng,Q. etal. Methylation of H3lysine 79 is
mediated by a new family of HMTases without
a SET domain. Curr. Biol. 12, 10521058 (2002).
10. Bannister,A.J., Schneider,R. & Kouzarides,T. Histone
methylation: dynamic or static? Cell 109, 801806
(2002).
11. Shi,Y. etal. Histone demethylation mediated by the
nuclear amine oxidase homolog LSD1. Cell 119,
941953 (2004).
This is the first report to show the existence of a
PKDM.
12. Tsukada,Y. etal. Histone demethylation by a family of
JmjC domain-containing proteins. Nature 439,
811816 (2006).
13. Hamamoto,R. etal. Enhanced SMYD3 expression is
essential for the growth of breast cancer cells. Cancer
Sci. 97, 113118 (2006).
14. Kotake,Y. etal. pRB family proteins are required for
H3K27 trimethylation and Polycomb repression
complexes binding to and silencing p16INK4 tumor
suppressor gene. Genes Dev. 21, 4954 (2007).
15. McCabe,M.T. etal. EZH2 inhibition as a therapeutic
strategy for lymphoma with EZH2activating
mutations. Nature 492, 108112 (2012).
This study describes the importance of somatic
mutations in PKMTs in developing anticancer drugs.
16. Fiskus,W. etal. Highly effective combination of LSD1
(KDM1A) antagonist and pan-histone deacetylase
inhibitor against human AML cells. Leukemia 28,
21552164 (2014).
17. Takawa,M. Validation of the histone methyltransferase
EZH2 as a therapeutic target for various types of
human cancer and as a prognostic marker. Cancer Sci.
102, 12981305 (2011).
18. Sasaki,M., Yamaguchi,J., Itatsu,K., Ikeda,H. &
Nakanuma,Y. Over-expression of polycomb group
protein EZH2 relates to decreased expression of
p16INK4a in cholangiocarcinogenesis in hepatolithiasis.
J.Pathol. 215, 175183 (2008).
19. Cho,H.S. etal. Enhanced expression of EHMT2 is
involved in the proliferation of cancer cells through
negative regulation of SIAH1. Neoplasia 13,
676684 (2011).
20. Cho,H.S. etal. The JmjC domain-containing histone
demethylase KDM3A is a positive regulator of the
G1/S transition in cancer cells via transcriptional
regulation of the HOXA1 gene. Int. J.Cancer 131,
E179189 (2012).
21. Toyokawa,G. etal. The histone demethylase JMJD2B
plays an essential role in human carcinogenesis
through positive regulation of cyclin-dependent kinase
6. Cancer Prev. Res. (Phila) 4, 20512061 (2011).
22. Cho,H.S. etal. RB1 methylation by SMYD2 enhances
cell cycle progression through an Increase of RB1
phosphorylation. Neoplasia 14, 476486 (2012).
23. Cho,H.S. etal. Enhanced HSP70 lysine methylation
promotes proliferation of cancer cells through
activation of Aurora kinase B. Nature Commun. 3,
1072 (2012).
This study provides clear evidence that protein
lysine methylation plays a critical part in the
regulation of subcellular localization.
1.
www.nature.com/reviews/cancer
2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
73. Yang,J. etal. Reversible methylation of promoterbound STAT3 by histone-modifying enzymes. Proc.
Natl Acad. Sci. USA 107, 2149921504 (2010).
74. Kim,E. etal. Phosphorylation of EZH2 activates
STAT3 signaling via STAT3 methylation and promotes
tumorigenicity of glioblastoma stem-like cells. Cancer
Cell 23, 839852 (2013).
This study provides clear evidence that non-histone
lysine methylation is an important target of cancer
therapy invivo.
75. Takawa,M. etal. Histone lysine methyltransferase
SETD8 promotes carcinogenesis by deregulating
PCNA expression. Cancer Res. 72, 32173227
(2012).
76. Zhao,H. etal. Targeting tyrosine phosphorylation of
PCNA inhibits prostate cancer growth. Mol. Cancer
Ther. 10, 2936 (2011).
77. Chen,A. PARP inhibitors: its role in treatment of
cancer. Chin. J.Cancer 30, 463471 (2011).
78. Jaffe,J.D. etal. Global chromatin profiling reveals
NSD2 mutations in pediatric acute lymphoblastic
leukemia. Nature Genet. 45, 13861391 (2013).
This study describes the importance of somatic
mutations in PKMTs for developing anticancer
drugs.
79. Yin,S. etal. Exome sequencing identifies frequent
mutation of MLL2 in non-small cell lung carcinoma
from Chinese patients. Sci. Rep. 4, 6036 (2014).
80. Gossage,L. etal. Clinical and pathological impact of
VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in
clear cell renal cell carcinoma. Genes Chromosomes
Cancer 53, 3851 (2014).
81. Cleary,S.P. etal. Identification of driver genes in
hepatocellular carcinoma by exome sequencing.
Hepatology 58, 16931702 (2013).
82. Dubuc,A.M. etal. Aberrant patterns of H3K4 and
H3K27 histone lysine methylation occur across
subgroups in medulloblastoma. Acta Neuropathol.
125, 373384 (2013).
83. Jankowska,A.M. etal. Mutational spectrum analysis
of chronic myelomonocytic leukemia includes genes
associated with epigenetic regulation: UTX, EZH2, and
DNMT3A. Blood 118, 39323941 (2011).
84. Morin,R.D. Frequent mutation of histone-modifying
genes in non-Hodgkin lymphoma. Nature 476,
298303 (2011).
85. Wang,X.X. etal. Somatic mutations of the mixedlineage leukemia 3 (MLL3) gene in primary breast
cancers. Pathol. Oncol. Res. 17, 429433 (2011).
86. Gui,Y. Frequent mutations of chromatin remodeling
genes in transitional cell carcinoma of the bladder.
Nature Genet. 43, 875878 (2011).
87. Grasso,C.S. etal. The mutational landscape of lethal
castration-resistant prostate cancer. Nature 487,
239243 (2012).
88. Lindberg,J. etal. The mitochondrial and autosomal
mutation landscapes of prostate cancer. Eur. Urol. 63,
702708 (2013).
89. Ho,A.S. etal. The mutational landscape of adenoid
cystic carcinoma. Nature Genet. 45, 791798 (2013).
90. Kandoth,C. etal. Mutational landscape and
significance across 12 major cancer types. Nature
502, 333339 (2013).
91. Greiner,D., Bonaldi,T., Eskeland,R., Roemer,E. &
Imhof,A. Identification of a specific inhibitor of the
histone methyltransferase SU(VAR)39. Nature Chem.
Biol. 1, 143145 (2005).
92. Kubicek,S. etal. Reversal of H3K9me2 by a smallmolecule inhibitor for the G9a histone
methyltransferase. Mol. Cell 25, 473481 (2007).
93. Chang,Y. etal. Structural basis for G9alike protein
lysine methyltransferase inhibition by BIX01294.
Nature Struct. Mol. Biol. 16, 312317 (2009).
This study determined the crystal structure of the
catalytic SET domain of G9alike protein in complex
with the specific inhibitor BIX01294.
94. Liu,Y. & Gray,N.S. Rational design of inhibitors that
bind to inactive kinase conformations. Nature Chem.
Biol. 2, 358364 (2006).
95. Vedadi,M. etal. A chemical probe selectively inhibits
G9a and GLP methyltransferase activity in cells.
Nature Chem. Biol. 7, 566574 (2011).
96. Ferguson,A.D. etal. Structural basis of substrate
methylation and inhibition of SMYD2. Structure 19,
12621273 (2011).
This study describes a drug development strategy
for inhibitors of a PKMT using a non-histone
protein as a substrate.
97. Knutson,S.K. etal. A selective inhibitor of EZH2
blocks H3K27 methylation and kills mutant lymphoma
cells. Nature Chem. Biol. 8, 890896 (2012).
REVIEWS
142. Ruault,M., Brun,M.E., Ventura,M., Roizes,G. & De
Sario,A. MLL3, a new human member of the TRX/
MLL gene family, maps to 7q36, a chromosome region
frequently deleted in myeloid leukaemia. Gene 284,
7381 (2002).
143. Okada,Y. etal. hDOT1L links histone methylation to
leukemogenesis. Cell 121, 167178 (2005).
144. Nguyen,A.T., Taranova,O., He,J. & Zhang,Y. DOT1L,
the H3K79 methyltransferase, is required for
MLLAF9mediated leukemogenesis. Blood 117,
69126922 (2011).
145. Bernt,K.M. & Armstrong,S.A. A role for DOT1L in
MLL-rearranged leukemias. Epigenomics 3, 667670
(2011).
146. Yamada,D. etal. Role of the hypoxia-related gene,
JMJD1A, in hepatocellular carcinoma: clinical impact
on recurrence after hepatic resection. Ann. Surg.
Oncol. 19, S355S364 (2012).
147. Guo,X. etal. The expression of histone demethylase
JMJD1A in renal cell carcinoma. Neoplasma 58,
153157 (2011).
148. Kogure,M. etal. Deregulation of the histone
demethylase JMJD2A is involved in human
carcinogenesis through regulation of the G1/S
transition. Cancer Lett. 336, 7684 (2013).
149. Berry,W.L., Shin,S., Lightfoot,S.A. & Janknecht,R.
Oncogenic features of the JMJD2A histone
demethylase in breast cancer. Int. J.Oncol. 41,
17011706 (2012).
150. Wang,H.L. etal. Expression and effects of JMJD2A
histone demethylase in endometrial carcinoma.
Asian Pac. J.Cancer Prev. 15, 30513056 (2014).
151. Hu,C.E., Liu,Y.C., Zhang,H.D. & Huang,G.J.
JMJD2A predicts prognosis and regulates cell growth
Acknowledgements
DATABASES
National Cancer Institute Drug Dictionary:
http://www.cancer.gov/drugdictionary
Pathway Interaction Database: http://pid.nci.nih.gov
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