(10) cancer cromatina y edad

7/17/2019 (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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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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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

suf

fici

ent

to

acc

ura

tel

!

deter

mi

ne

tiss

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

!lated

are fre-

'uentl!

h!perm

eth!lat

ed in

cancer

"#1%.

Because C>I

meth!l

ation

has

een

oser,

ed in

se,eral

tumor

suppres

-sor

genes#

it haseen

suggest

ed that

aerran

t C>I

meth!l

ation is

a maI

promot

er

h!permeth!lati

on in

aged

tissues

and

cancer

cells

ma!

suggest

that

meth!l

ation of

C>Is

predisp

oses

aged

cells to

neoplas

tic

transfo

rmatio

n

"11#$0%

. ?or

instanc

e#

similarpattern
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5/34

s

of

C>

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the

est

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8

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l

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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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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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7/34

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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8/34

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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9/34

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


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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11/34



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


13/34


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

4 Daldmann# T. and Achneider# *. 8$01: Targeting histone modifications =

epigenetics in cancer. Curr. Epin. Cell Biol. $# 14=149

5 Ba!lin# A.B. and Mones# P.). 8$011: ) decade of e+ploring the cancer

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

8 @ope5-Etin# C. et al. 8$01: The

hallmar/s of aging. Cell 1#

119= 1$13

9 uidoro# C. et al. 8$01: )gingepigenetics7 causes and

conse'uences.

ol. )spects ed. # 36=341

10 Putiri# .@. and *oertson#G.(. 8$011: pigenetic

mechanisms and genome stailit!.

Clin. pigenetics $# $99=1

3
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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.

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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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characteri5es (N)-h!permeth!lated genes in colon cancer cells. through a path&a! related to calorie restriction. Proc. Natl. )cad. Aci.Cancer *es. 64# 3=39 F.A.). 101# 1994=1600

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