(10) Cancer Cromatina y EdaD
Transcript of (10) Cancer Cromatina y EdaD
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TICB-1069; No. of Pages 9
Review
Common features of chromatin in
aging and cancer: cause orcoincidence?Linda Zane
*, Vivek Sharma
*, and Tom Mistei
!ationa Cancer "nstitute, !ationa "nstitutes of #eath, $ethesda, M% &'()&, S+
+ge is a maor risk factor for cancer- +terations in%!+ meth.ation, histone modifications, chromatinstruc/ture, and e0igenetic reguator. mechanismsare 0romi/nent hamarks of 1oth the aging
0rocess and cancer- "ntriguing. 2 or 0ossi1.coincidenta. 2 severa chro/matin features arecommon 1etween aging and cancer- #ere we askwhether, and if so how, aging/associatedchromatin modifications contri1ute to tumorsusce0ti/1iit. and tumorigenesis-
+t the intersection of aging, cancer, and chromatin
The functional properties of genomes are shaped ! the
secondar! features of chromatin "1#$%.The hard-&ired
hereditar! information contained in the primar!
genome se'uence is modified ! (N) meth!lation#
histone mod-ifications# higher-order chromatin
structure# noncoding *N)s# and epigenetic regulator!mechanisms "1#$%. These chromatin features determine
and modulate gene e+pres-sion programs and perform
critical regulator! roles in numerous iological
processes# particularl! in response to en,ironmental
factors such as nutrition and chemical pollutants
rele,ant to disease "#%.
Changes in chromatin features ha,e een closel!
lin/ed to cancer susceptiilit! and tumor gro&th "#6%.
an! cancer cells and tissues e+hiit gloal and2or
local changes in histone modifications and chromatin
structure. Chro-matin alterations are li/el! to contriute
sustantiall! to tumorigenesis and numerous e+amplesin &hich chroma-tin changes dri,e tumorigenesis ha,e
een descried "#6%.Changes in chromatin features#
rought aout ! en,iron-mental insult and intrinsic
e,ents# ma! influence multiple steps of tumorigenesis
! stimulating cell proliferation# promoting genomic
instailit!# and facilitating cellular transformation "3%.
Chromatin changes and epigenetic alterations are
also one of the prominent hallmar/s of aging cells and
organ-isms "4%. The progressi,e loss of ph!sical
function o,er time that characteri5es the aging process
is often accompanied ! epigenetic modifications.
+posure to en,ironmental to+ins and endogenous
stress has een lin/ed to aging# possil! ,ia
interference &ith chromatin
regulator!
Corresponding author7
isteli# T. 8
mistelitmail.nih.go,:.These
authorscontriutede'uall!.
')3&/()&45
6u1ished 1. 7sevier Ltd-
htt0:55d8-doi-org59'-9'935-tc1-&'94-'-''9
mechanisms "9%.It has also
een speculated that
epigenetic alterations
contriute to age-related
changes in iological
functions as &ell as to the
oser,ed increased genomic
instailit! in aging
organisms and cells "3#10%.
Because ad,anced age is
a primar! ris/ factor for can-
cer# and ecause epigenetic
alterations are hallmar/s of
oth aging and cancer#
o,ious 'uestions are
&hether aging-associated
chromatin changes acti,el!
contriute to cancer
susceptiilit! and gro&th and&hether these changes are
the asis for the strong age
dependence of cancer or
&hether the! are merel!
coincidental changes &ith no
functional lin/s "11%. In this
re,ie &e highlight se,eral
epigenetic features that are
prominentl! affected in oth
mammalian aging and
cancer# and &e discuss their
potential roles and
mechanisms in dri,ing age-related tumorigenesis.
%!+ meth.ation
(N) meth!lation is one of
the ma: dinucleotides has
een implicated in regulating
gene e+pression ! gene
silencing and epigenetic
memor! in di,erse iological
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processes "1$%. Three (N) meth!ltrans-ferases
8(NTs: mediate this modification7 (NTa and
(NT function as de no,o meth!ltransferases and
(NT1 acts as a maintenance meth!ltransferase "6#4%.
Changes in (N) meth!lation patterns ha,e een docu-
mented in aging and in cancer 8 Tale 1:. Both
processes are characteri5ed ! loss of meth!lation
8(N) h!pometh!la-tion: from Cp>s located in repeat
regions of the genome and concomitant increases in
(N) meth!lation 8(N) h!permeth!lation: in Cp>s
located in the promoter regions of genes /no&n as Cp>
islands 8C>Is: 8?igure 1 and Tale 1: "#9#1#1%.
The same phenomenon of
(N) h!pometh!-lation and
focal h!permeth!lation is
oser,ed in senes-cence# a
state &hen cells cease to
di,ide and &hich has een
suggested to represent
cellular aging and implicated
as oth a tumor-protecti,e
and tumor-promoting
mechanism "1%.
@oss of c!tosine
meth!lation from the repeat
regions of the genome# such
as in long interspersed
nucleotide elements 8@INs:
and short interspersed
nucleotide elements 8AINs:#
&hich comprise
appro+imatel! 0 of the
genome# significantl!
contriutes to a gloal
decrease in (N)
meth!lation oser,ed during
aging "16=$1%.Trends in Ce $ioog. 88 ;&'94< 92)
9
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TICB-1069; No. of Pages 9
Review Trends in Ce $ioog. 888 8888, Vo- 888, !o- 8
Ta1e 9- Chromatin features in aging and cancer
+ging Cancer
%!+ meth.ation
%!+ h.0ometh.ation = L"!7 and S"!7 regions >932&9 = L"!7 and S"!7 regions >9@,9),&42&3
%!+ h.0ermeth.ation = CA"s >&',&9,@@,@B = CA"s >B,94,@42@3
#istone modifications
#493ac D "n vitro in aged c.cing human fi1ro1asts >B& D Various cancers >BB
#4&'me@ D "n vitro in aged c.cing human fi1ro1asts >B& D Various cancers >BB,4
= "n vivo in iver and kidne. of eder. rats >( D Rat mode >@
= #utchinson2Aiford 0rogeria ces >
#@)ac = "n vitro in aged c.cing human fi1ro1asts >B& = Lung cancer >(9
D $reast cancer >('
#@4me@ = "n vitro in aged c.cing human fi1ro1asts >B& D $reast cancer >949
= Aio1astoma >9@3,rena ce carcinomas >9@
#@)me@ D "n vitro in aged c.cing human fi1ro1asts >B& = #umans >)9
D #utchinson2Aiford 0rogeria ces >
D 6ancreatic carcinomas >9@(
#@&me@ = 7so0hagea sEuamous ce carcinoma >9@)
D Senescent ces >)) D 6ediatric high/grade giomas >9'&
ncR!+
#FT+"R !%a = $reast >994
#FTT"6 !% = Liver, eukemia >993,99
CT$69/+S !% = 6rostate >99(
+!R+SSG9 !% = $reast, 0rostate >99)
H"ST D Senescence >9&& !%
M+L+T9 D Senescence >9&& = Various cancers >94'
S+L/R!+9 D Senescence >9&& !%
+!R"L D Senescence >9&3 = 6rostate, eukemia >9&3,9&
Red, reduction of indicated featureI green, increase of indicated feature-a!ot
determined-
!pometh!lation of these repeat regions is associated &ith the
decline of organ function during aging "13#14%. >loal (N)
h!pometh!lation of repeat-rich regions is also oser,ed in
numerous cancers "1#19%.@IN-1 h!po-meth!lation is correlated
&ith increased ris/ of de,elop-ing cancer and poor sur,i,al of
cancer patients# as seen# for e+ample# in head and nec/ s'uamous
cell carcinoma# m!eloma# and ladder cancer "1#$$=$6%. (N)
h!po-meth!lation of repeat elements has also een proposed to
contriute to cellular transformation ! promoting chromosomal
rearrangements and ele,ating mutation rates "1#$3=$9%. )part
from h!pometh!lation of repeat
elements# loss of meth!lation
from genic regions also causes
aerrant gene e+pression and
promotes tumori-genesis
"1#0%.
>loal (N)
h!pometh!lation associated
&ith aging and senescence is#
intriguingl!# accompanied !
local (N) h!permeth!lation at
C>Is "1#$0#$1%. C>I
h!permeth!la-tion in promoter
regions generall! aids in gene
silencing ! recruitment of
en5!matic machiner! to
estalish silent chromatin ,ia
proteins such as meth!l-Cp>-
inding domain 8B(: or ma!
loc/ the inding of chromatin
modifiers and transcription
factors to meth!lated (N)
"1$#1#$%. C>I meth!lation
patterns are altered in
oung /
normal
ssue
Promoter
CGIs
Promoter
DNA
methylaon
TR
Gigure 9- Changes in %!+ meth.ation during aging and
cancer- C.tosine20hos0hate2guanine ;C0A< dinuceotides
ocated in the 0romoter regions of genes known as C0A
isands ;CA"s< show increased 0ro0ensit. for meth.ation
during aging and cancer- C0As ocated in the re0eat
regions of the genome, 1. contrast, genera. show oss of
meth.ation with age and in cancer-&
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TICB-1069; No. of Pages 9
Review
a
pre
dicta
le
fas
hio
n
dur
ing
agi
ng
an
d
ana
l!sis
of
the
me
th!
lati
on
stat
us
of
def
ined
C>
Is
is
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ent
to
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ura
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!
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mi
ne
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ue
age
"
%.
!
per
me
th!
lati
on
als
o
appears
to e
rele,an
t to
cancer#
as
indicat
ed !
the fact
thatC>Is
that are
normal
l!
unmeth
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are fre-
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eth!lat
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"#1%.
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it haseen
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aerran
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meth!l
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a maI
promot
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h!permeth!lati
on in
aged
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and
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ma!
suggest
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meth!l
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C>Is
predisp
oses
aged
cells to
neoplas
tic
transfo
rmatio
n
"11#$0%
. ?or
instanc
e#
similarpattern
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s
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the
est
rog
enrec
ept
or
8
*:
ge
ne
occ
ur
dur
ing
agi
ng
innor
ma
l
col
on
tiss
ue
an
d
in
col
on
cancer
cel
ls
"
%
an
d
e+
og
en
ous
e+
pre
ssion
of
the
*
sup
pre
sse
s
col
on
can
cer
cell
gro
&th in
,itro#
suggest
ing that
aging-
associa
ted re-
pressio
n of
*
e+press
ion
facilitates
tumori
genesis
"%. In
additio
n#
promot
ers of
genes
that are
targets
of the
repres-
si,epol!co
m
group
of
chroma
tin
protein
s are
meth!l
ated
during
aging
"6%# asis the
case
for
numero
us
cancers
# &here
chroma
tin
modifi
cations
!
pol!co
mgroup
pro-
teins
o,erlap
&ith
(N)
h!perm
eth!lat
ed
genes
"3#4%
.
Interestingl!#
some
of
these
genes
are
in,ol,e
d in
stem
cell
differe
ntiation
#
suggest
ing thatage-
depend
ent
meth!l
a-tion
of
pol!co
m
target
genes
ma!
predisp
ose the
aginggenom
e to
neoplas
tic
transfo
rmatio
n !
staili5
ing
stem
cell-
li/e
features "6%.
The
lin/
et&ee
n
aging#
cancer#
and
(N)
h!perm
eth!lati
on is
also
support
ed !
the
intrigui
ng fact
that
genes
&hose
mutatio
ns are
associa
ted
&ith
ag-gressi,
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7/17/2019 (10) Cancer Cromatina y EdaD
6/34
e
pre
ma
tur
e
agi
ng
ph
en
ot!
pes
#
such
as
D
*N
in
De
rne
r
s!n
dro
me
an
d
@
N
)#
the
cau
sati
,e
age
nt
of
u
tch
inson
=
>il
for
d
Pro
ger
ia
A!
ndr
om
e#
are
fre'u
ent
l!
sile
nce
d
!
(
N
)
me
th!
lation
in
a &ide
,ariet!
of
cancers
"9#0%
. Ef
note in
this
conte+t
is the
fact
that
someof
these
premat
ure
aging
disorde
rs are
charact
eri5ed
!
increas
ed
tumor
susceptiilit!
"1%.
The
mecha
nisms
underl!
ing the
opposi
ng fate
of
(N)meth!l
ation
8i.e.#
(N)
h!pom
eth!lati
on of
repeate
d
se'uen
ces and
simulta
neous
h!perm
eth!lati
on of
C>Is:
oser,
ed
during
aging
and
cancer
are
un/no
&n
"11#1%. The
(N)-
meth!l
ating
acti,it!
of oth
the
mainte
nance
meth!lt
ransfer
ase
(NT
1 andthe de
no,o
meth!lt
rans-
ferases
(NT
a and
(NT
is
altered
during
aging
and
neoplastic
transfo
rmatio
n
"$#%
.
Dhere
as the
acti,iti
es of
(NT
1 and
(NTa
decreas
e#
(NT
acti,it!
increas
es in
cells
approa
ching
senesce
nce
"$#%#
suggest
-ing
that
gloal
(N)
h!pom
eth!lati
on in
aging
cells is
due to
reduced
(NT
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7/17/2019 (10) Cancer Cromatina y EdaD
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1
act
i,it
!.
(
N
T1
has
als
o
ee
nrep
ort
ed
to
e
mi
slo
cal
i5e
d
in
sen
esc
entcel
ls#
pos
si
l!
trig
ger
ing
h!
po
me
th!
lation
at
spe
cifi
c
ge
no
mi
c
site
s
"1
%.
C>I
h!
per
me
th!
lati
on
dur
ing
agi
ng
is
assum
ed
to e
due to
de
no,o
acti,it!
of
(NT
. In
contras
t to
aging
cells#
&hichsho&
reduce
d
(NT
1
acti,it!
#
se,eral
tumors
sho&
(NT
1
o,ere+
pression and
its
acti,it!
has
een
lin/ed
to
Trends in Ce$ioog. 8888888, Vo- 888,!o- 8
C>I
h!perm
eth!lati
on
"%#
althoug
h
(NT1
o,ere+
pres-
sion is
not
al&a!s
associa
ted
&ith
C>I
h!perm
eth!lati
on
"%.(NT
and
(NT
a are
also
fre'uen
tl!
o,ere+-
pressed
in
tumors#
&ith
(NT
general
l! at
higher
le,els
than
(NT
a
"6%. It
therefo
re
appears
that# al-
thoughaged
cells
and
cancer
cells
share
se,eral
commo
n
feature
s of
(N)
meth!l
ation#
no
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7/17/2019 (10) Cancer Cromatina y EdaD
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co
m
mo
n
mi
sre
gul
ati
on
of
the
(
N
)
me
th!
lati
on
ma
chi
ner
!
is
e,i
de
nt#
sugges
tin
g
tha
t
oth
er#
as-
!et
-
un
/n
o&
n
fac
tor
s
det
er
mi
ne
the
me
th!
l-
ati
onpat
ter
ns
of
agi
ng
an
d
can
cer
cel
ls.
#i
stonemodifications
Core
histone
s
throug
hout
the
genom
e are
modifi
ed at
numero
us
amino
acid
residue
s ! a
di,erse
set of
chemic
al
modifi
cations#
mostpromin
entl!
acet!la
tion#
meth!l
ation#
ui'uit
!lation#
AFE
!lation#
and
phosph
or!lati
on
"3%.
The
additio
n or
remo,a
l of
these
modifi
cations
creates
inding
sites
forchroma
tin
protein
s and
often
alters
the
degree
of
compa
ction of
chroma
tin
"3#4%.
)erra
nt pat-
terns of
histone
modifi
cations
are
hallmar
/s of
oth
aging
"4% and
cancer
"9% 8
Tale
1:.
Atud
ies in
!east
and in
senesce
nt
mamm
alian
cells
suggest
that
aging
is
accom
panied
! a
reducti
on of
gloal
histone
le,els#
thus
affecting
chroma
tin
structur
e.
iston
e #
#
$)#
and
$B
le,els
are
decreased in
replicat
i,el!
old
uddin
g !east
cells
"0#1%
and in
senesce
nt
human
firolasts
generat
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7/17/2019 (10) Cancer Cromatina y EdaD
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ed
thr
ou
gh
eit
her
rep
lic
ati
,e
sen
es-
cen
ce
or
on
co
ge
ne-
ind
uce
d
sen
esc
enc
e
"$#
%.
>e
ner
al
los
s
of
cor
e
his
ton
es
is
tho
ug
ht
to
lea
d
to
nu
cle
oso
me
de
pletio
n
an
d
an
acc
om
pa
n!i
ng
ge
no
me
-&i
de
increas
e in
gene
e+-
pressio
n#
ele,ate
d le,els
of
(N)
damag
e#
retrotra
nsposi-
tion#
large-
scale
chromo
some
rearran
gement
# and
translo
cation
during
!eastaging
"0#%
.
Ene
of the
most
promin
entl!
altered
histone
modifi
ca-tionis
G16
acet!la
tion#
&hich
is
reduce
d
during
the
aging
process
"$% as
&ell asin
,arious
t!pes
of
tumors
"%.
G16
acet!la
tion
has
een
implica
ted inhigher-
order
chroma
tin
organi5
ation
"6#3%
and
pla!s
an im-
portant
role in
the
(N)
damage
respons
e#
allo&in
g for
the
possii
lit! that
an
aging-
associa
ted
decreas
e inG16
ac
promot
es
genomi
c
instail
it!
"4=
60%.
)lthou
gh
multiple#
partiall
!
redund
ant
histone
acet!ltr
ansfera
ses
promot
e
acet!la
tion of
G16# Airt1
appears
to e
the
ma
-
7/17/2019 (10) Cancer Cromatina y EdaD
10/34
att
ent
ion
in
the
agi
ng
fiel
d
du
e
to
report
s
tha
t
its
in,
ert
er
ate
ho
mo
log
#
Air$#
pro
mo
tes
lon
ge
,it
!
in
!ea
st#
&o
rms#
an
d
flie
s
"6
=
6%
.
o
&e
,er
#
altho
ug
h
o,
er-
e+
pre
ssi
on
of
Airt1
impro,
es
,arious
aspects
of
health
during
aging
and
promot
es
sur,i,al in a
mouse
model
of
genomi
c
instail
it!#
Airt1
does
not
appear
to
increase
longe,i
t! in
mamm
als
"66#63%
.
Be!on
d its
role in
aging#
Airt1
alsoseems
to pla!
a role
in
cancer
"64%.
Its
e+pres-
sion is
upregul
ated in
a &ide
range
ofcancer
t!pes
includi
ng
leu/em
ia#
reast#
prostat
e# lung#
colon#
and
gastric
"64#69%
. The
reasons
&h!
Airt1
ma!
promot
e
longe,i
t! in
lo&erorganis
ms ut
promot
es
tumor
gro&th
in
higher
organis
ms are
un/no
&n.
Tri
meth!l
ation of
histone
on
l!sine
$0 is
also
affect-
ed in
oth
aging
andcancer.
G$0
me is
highl!
enriche
d at
pericen
tric
heteroc
hromat
in#
telomer
es#
imprinted ge-
nome
regions
# and
repetiti
,e
elemen
ts#
suggest
ing that
@
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TICB-1069; No. of Pages 9
Review Trends in Ce $ioog. 888 8888, Vo- 888, !o- 8
this modification is in,ol,ed in transcriptional silencing "30#31%.
@e,els of G$0me are decreased in man! can-cers# including
li,er# reast# ladder# and lung "3$=3%. @oss of G$0me in
cancer ma! e due to reduced e+pression of the G$0-specific
meth!ltransferase Au,-$0h# as oser,ed in hepatocarcinoma in a
rat model and in reast cancer cells "3#3%.Interestingl!# Au,-$0h has een implicated in the maintenance of genome stail-it!
"3% and Au,-$0h doule-/noc/out mice present &ith
chromosomal aerrations due to less-efficient (N) dou-le-strand
rea/ repair "36%. G$0me le,els are also reduced in late-
passage c!cling human diploid firolasts 8(?s: "$%.
?urthermore# e+ogenous e+pression of telo-merase does not restore
G$0me le,els# suggesting that replicati,e senescence and (N)
damage responses are not responsile for ele,ation of trimeth!l-
G$0 in (?s "$%.B! contrast# upregulation of G$0me has
een oser,ed in the premature aging disorder utchin-son=>ilford
Progeria A!ndrome "33% and in the li,ers and /idne!s of elderl!
rats "34%. Ef note# in contrast to senes-cent firolasts deri,ed !
e+tensi,e passaging "$%# G$0me le,els &ere found to e
ele,ated in *)A-in-duced senescent cells "39%# suggesting
differences in se-nescence states depending on ho& senescence is
induced "1%.
Ether aging-associated histone modifications include G9
acet!lation and trimeth!lation of G# G9# and G$3.
Changes in these modifications ha,e een oser,ed in cancers#
although their le,els ,ar! depending on tumor t!pe 8Tale 1:. ?or
e+ample# reast cancer cells sho& lo& G9ac le,els "40%#&hereas lung cancer cells sho& high le,els "41%.)n increase in
G9ac# the su-strate for the histone deacet!lase 8()C: Airt6
"4$%# &hich increases longe,it! in mammals# occurs in aged c!cling
human firolasts in ,itro "$%. ice deficient in AI*T6 e+hiit
accelerated aging "4%# &hereas transgenic mice o,ere+pressing
AI*T6 ha,e a longer lifespan than control animals "4%. These
findings are interesting gi,en that much e,idence points to a role of
AI*T6 as a tumor suppressor# particularl! ,ia its role in (N) repair
and genomic stailit!. ouse emr!onic firolasts from AI*T6-
deficient mice e+hiit chromosomal aerra-tions including
fragmented chromosomes and detached centromeres "4%.)long
&ith G9ac le,els# AI*T6 le,els ,ar! depending on the tumor
t!pe. AI*T6 is do&nregulated in se,eral human cancers# such as
pancreatic cancer# colorectal cancer# and hepatocellular carcinoma
8CC: "64%# ut upregulated in prostate cancer "4%. It has een
suggested that AI*T6 e+erts its longe,it! function ! reducing
harmful le,els of G9ac "46%.
)ged cells are also characteri5ed ! increased le,els of
Gme# a mar/ of acti,e chromatin# and a decrease of
G9me# a mar/ of repressed chromatin "$%. B! con-trast#
G9me le,els are ele,ated in oncogene-induced senescent cells
and the mar/ accumulates in compacted heterochromatin foci"43#44%. G9me has een associat-ed &ith oth positi,e and
negati,e patient prognosis in
se,eral cancers depending on
tumor t!pe# including acute
m!eloid leu/emia "49%#
sali,ar! adenoid c!stic
carcinoma "90%# and gastric
adenocarcinoma "91%.
Trimeth!lation of
G also seems to pla! a role
in cancer# ecause the gene
encoding one of the en5!mes
that catal!5e the meth!lation of
G# the mi+ed-lineage
leu/emia 8@@: protein l!sine
meth!ltransferase# is
commonl! translocated inleu/e-mias# leading to aerrant
e+pression of de,elopmental
and hematopoietic genes "9$%.
) role of Gme in aging is
supported ! the fact that
deficienc! in a memer of the
)sh-$ comple+# &hich
trimeth!lates G# prolongs
the lifespan of Caenorhaditis
elegans and con,e!s transge-
nerational longe,it! "9%.
Based on oser,ations in
mouse cells# Gme alsoappears to e interdependent
&ith the repressi,e mar/
G$3me# &hich is catal!5ed
! pol!com-group proteins#
during de,elopment and cell
differentiation "9=96%. The
genome-&ide distriution
patterns of these t&o histone
modifications differ et&een
senescent and proliferating
cells "93% and the! e+hiit
i,alent regions enriched in
G$3me and Gme atlamin-associated domains and
G$3me-depleted regions#
respecti,el!# referred to as
Hmesas and Hcan!ons et&een
lamin-associated domains
corresponding to genes and
enhancers "93%. These mesas
o,erlap &ith (N)
h!pometh!lation regions
oser,ed in senescent "1% and
cancer cells "94%. @oss of
G$3me and Gme
mesas has also een reported in
utchinson= >ilford Progeria
A!ndrome "33#93% and in
senescent cells "99%.
G$3me is a target of
J$# a meth!ltransferaseand
component of the pol!com
repressi,e comple+ $ 8P*C$:
&hose e+pression is decreased
in senescent cells "99%.
Con,ersel!# o,ere+pression of
J$ and G$3me has
een associated &ith poorsur,i,al in gastric# reast# and
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prostate cancers and cutaneous melanoma "100#101%. ) reduction
in G$3me in pediatric high-grade gliomas haroring t&o
mutations# G$3 and >*2K# in histone . has also een
reported and this reduction of G$3me has een associated &ith
(N) h!pometh!la-tion "10$%. In cancer cells# G$3 seems to
target loci for de no,o (N) meth!lation "10%. o&e,er# the
relationship et&een G$3me# (N) meth!lation# and cancer is
unclear ecause silencing of genes mar/ed ! trimeth!l-G$3 in
the asence of (N) meth!lation has also een reported "10%.
ost of the human studies on histone post-translational
modifications in cancer and aged cells are correlati,e and it is
un/no&n &hether these modifications are causati,e or represent
merel! a conse'uence of these
processes. In addition to the
o,ious local effects that
changes in his-tone-
modification patterns ma! ha,e
on indi,idual tumor-promoting
or -repressing genes# one of the
most li/el! scenarios for ho&
aging-associated chromatin
modifica-tions might contriute
to tumorigenesis is ! inducing
changes to higher-order
chromatin structure that in turnma! ma/e chromatin
susceptile to damage "10%.
Because one of the ma
-
7/17/2019 (10) Cancer Cromatina y EdaD
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TICB-1069; No. of Pages 9
Review
Long
noncodingR!+s;ncR!+senet. (e,. $# 14=190
2 isteli# T. 8$01: The cell
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iolog! of genomes7 ringing the doule heli+ to life. Cell 1$# 1$09=1$1$
3 Tollefsol# T.E. 8$01: (ietar! epigenetics in cancer and aging. Cancer Treat.*es. 19# $3=$63
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epigenetics in cancer. Curr. Epin. Cell Biol. $# 14=149
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epigenome = iological and translational implications. Nat. *e,. Cancer 11#
3$6=3
6 (a&son# .). and Gou5arides# T.8$01$: Cancer epigenetics7 frommechanism to therap!. Cell 10#1$=$3
7 Cruic/shan/s# .). and )dams#P.(. 8$011: Chromatin7 a
molecular interface et&een
cancer and aging. Curr. Epin.
>enet. (e,. $1# 100= 106
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hallmar/s of aging. Cell 1#
119= 1$13
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conse'uences.
ol. )spects ed. # 36=341
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Clin. pigenetics $# $99=1
3
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TICB-1069; No. of Pages 9
Review Trends in Ce $ioog. 888 8888, Vo- 888, !o- 8
11 ?raga# .?. et al. 8$003: Cross-tal/ et&een aging and cancer7 the 9 )grelo# *. et al. 8$006: pigenetic inacti,ation of the premature agingepigenetic language. )nn. N. O. )cad. Aci. 1100# 60=3 Derner s!ndrome gene in human cancer. Proc. Natl. )cad. Aci. F.A.).
1$ (eaton# ).. and Bird# ). 8$011: Cp> islands and the regulation of 10# 44$$=44$3transcription. >enes (e,. $# 1010=10$$ 0 )grelo# *. et al. 8$00: Inacti,ation of the lamin )2C gene ! Cp>
1 hrlich# . 8$009: (N) h!pometh!lation in cancer cells. pigenomics island promoter h!permeth!lation in hematologic malignancies# and1# $9=$9 its association &ith poor sur,i,al in nodal diffuse large B-cell
1 Ba!lin# A.B. and Ehm# M.. 8$006: pigenetic gene silencing in cancer l!mphoma. M. Clin. Encol. $# 90=93= a mechanism for earl! oncogenic path&a! addiction Nat. *e,. 1 oei 10
island lin/s ageing and neoplasia in human colon. Nat. >enet. 3# 6= 6$ Pruitt# G. et al. 8$006: Inhiition of AI*T1 reacti,ates silenced cancer0 genes &ithout loss of promoter (N) h!permeth!lation. P@oA >enet.
6 Teschendorff# ).. et al. 8$010: )ge-dependent (N) meth!lation of $# e0
genes that are suppressed in stem cells is a hallmar/ of cancer. 6 Ainclair# (.). and >uarente# @. 81993: +trachromosomal r(N)>enome *es. $0# 0=6 circles = a cause of aging in !east. Cell 91# 10=10$3 c>ar,e!# G.. et al. 8$004: (efining a chromatin pattern that 6 *ogina# B. and elfand# A.@. 8$00: Air$ mediates longe,it! in the fl!
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