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Review
Review
Cancer
H3K9ac
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H3K4me3
H3K9me3
H3K27me3
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# Senescence
# Senescence
# Senescence
# Senescence
DNA methylation
DNA hypomethylation
DNA hypermethylation
Histone modifications
H4K16ac
H4K20me3
lncRNA
HOTAIR
HOTTIP
CTBP1-AS
ANRASSF1
XIST
MALAT1
SAL-RNA1
ANRIL
[122]
[122]
[122]
[126]
Not determined.
Promoter
Exon
CGIs
Promoter
Exon
Exon
Intragenic repeats
Intragenic repeats
CGIs
Exon
DNA methylaon
TRENDS in Cell Biology
Figure 1. Changes in DNA methylation during aging and cancer. Cytosinephosphateguanine (CpG) dinucleotides located in the promoter regions of genes known as CpG
islands (CGIs) show increased propensity for methylation during aging and cancer. CpGs located in the repeat regions of the genome, by contrast, generally show loss of
methylation with age and in cancer.
Review
a predictable fashion during aging and analysis of the
methylation status of 353 defined CGIs is sufficient to
accurately determine tissue age [33]. Hypermethylation
also appears to be relevant to cancer, as indicated by the
fact that CGIs that are normally unmethylated are frequently hypermethylated in cancer [5,14]. Because CGI
methylation has been observed in several tumor suppressor genes, it has been suggested that aberrant CGI
methylation is a major contributor to neoplastic transformation via the stabilization of transcriptional repression, thereby leading to loss of function of tumor
suppressor genes [11,14]. CpG hypermethylation of promoters also affects the expression of various noncoding
RNAs that may have a role in malignant transformation
[5,34].
The phenomenon of CGI promoter hypermethylation in
aged tissues and cancer cells may suggest that methylation
of CGIs predisposes aged cells to neoplastic transformation
[11,20]. For instance, similar patterns of CGI methylation
of the estrogen receptor (ER) gene occur during aging in
normal colon tissue and in colon cancer cells [35] and
exogenous expression of the ER suppresses colon cancer
cell growth in vitro, suggesting that aging-associated repression of ER expression facilitates tumorigenesis [35]. In
addition, promoters of genes that are targets of the repressive polycomb group of chromatin proteins are methylated
during aging [36], as is the case for numerous cancers,
where chromatin modifications by polycomb group proteins overlap with DNA hypermethylated genes [37,38].
Interestingly, some of these genes are involved in stem cell
differentiation, suggesting that age-dependent methylation of polycomb target genes may predispose the aging
genome to neoplastic transformation by stabilizing stem
cell-like features [36]. The link between aging, cancer, and
DNA hypermethylation is also supported by the intriguing
fact that genes whose mutations are associated with aggressive premature aging phenotypes, such as WRN in
Werner syndrome and LMNA, the causative agent of
HutchinsonGilford Progeria Syndrome, are frequently
silenced by DNA methylation in a wide variety of cancers
[39,40]. Of note in this context is the fact that some of these
premature aging disorders are characterized by increased
tumor susceptibility [41].
The mechanisms underlying the opposing fate of DNA
methylation (i.e., DNA hypomethylation of repeated
sequences and simultaneous hypermethylation of CGIs)
observed during aging and cancer are unknown [11,13].
The DNA-methylating activity of both the maintenance
methyltransferase DNMT1 and the de novo methyltransferases DNMT3a and DNMT3b is altered during aging and
neoplastic transformation [42,43]. Whereas the activities
of DNMT1 and DNMT3a decrease, DNMT3b activity
increases in cells approaching senescence [42,43], suggesting that global DNA hypomethylation in aging cells is due
to reduced DNMT1 activity. DNMT1 has also been
reported to be mislocalized in senescent cells, possibly
triggering hypomethylation at specific genomic sites [15].
CGI hypermethylation during aging is assumed to be due
to de novo activity of DNMT3b. In contrast to aging cells,
which show reduced DNMT1 activity, several tumors show
DNMT 1 overexpression and its activity has been linked to
CGI hypermethylation [44], although DNMT1 overexpression is not always associated with CGI hypermethylation
[45]. DNMT3b and DNMT3a are also frequently overexpressed in tumors, with DNMT3b generally at higher
levels than DNMT3a [46]. It therefore appears that, although aged cells and cancer cells share several common
features of DNA methylation, no common misregulation of
the DNA methylation machinery is evident, suggesting
that other, as-yet-unknown factors determine the methylation patterns of aging and cancer cells.
Histone modifications
Core histones throughout the genome are modified at
numerous amino acid residues by a diverse set of chemical
modifications, most prominently acetylation, methylation,
ubiquitylation, SUMOylation, and phosphorylation [47].
The addition or removal of these modifications creates
binding sites for chromatin proteins and often alters the
degree of compaction of chromatin [47,48]. Aberrant patterns of histone modifications are hallmarks of both aging
[8] and cancer [49] (Table 1).
Studies in yeast and in senescent mammalian cells
suggest that aging is accompanied by a reduction of global
histone levels, thus affecting chromatin structure. Histone
H3, H4, H2A, and H2B levels are decreased in replicatively
old budding yeast cells [50,51] and in senescent human
fibroblasts generated through either replicative senescence or oncogene-induced senescence [52,53]. General loss
of core histones is thought to lead to nucleosome depletion
and an accompanying genome-wide increase in gene expression, elevated levels of DNA damage, retrotransposition, large-scale chromosome rearrangement, and
translocation during yeast aging [50,54].
One of the most prominently altered histone modification is H4K16 acetylation, which is reduced during the
aging process [52] as well as in various types of tumors
[55]. H4K16 acetylation has been implicated in higherorder chromatin organization [56,57] and plays an important role in the DNA damage response, allowing for
the possibility that an aging-associated decrease in
H4K16ac promotes genomic instability [5860]. Although
multiple, partially redundant histone acetyltransferases
promote acetylation of H4K16, Sirt1 appears to be the
major modifying enzyme [61,62]. Sirt1 is the focus of
much attention in the aging field due to reports that
its invertebrate homolog, Sir2, promotes longevity in
yeast, worms, and flies [6365]. However, although overexpression of Sirt1 improves various aspects of health
during aging and promotes survival in a mouse model of
genomic instability, Sirt1 does not appear to increase
longevity in mammals [66,67]. Beyond its role in aging,
Sirt1 also seems to play a role in cancer [68]. Its expression is upregulated in a wide range of cancer types
including leukemia, breast, prostate, lung, colon, and
gastric [68,69]. The reasons why Sirt1 may promote
longevity in lower organisms but promotes tumor growth
in higher organisms are unknown.
Trimethylation of histone H4 on lysine 20 is also affected in both aging and cancer. H4K20me3 is highly enriched
at pericentric heterochromatin, telomeres, imprinted genome regions, and repetitive elements, suggesting that
3
Review
this modification is involved in transcriptional silencing
[70,71]. Levels of H4K20me3 are decreased in many cancers, including liver, breast, bladder, and lung [7274].
Loss of H4K20me3 in cancer may be due to reduced
expression of the H4K20-specific methyltransferase
Suv4-20h, as observed in hepatocarcinoma in a rat model
and in breast cancer cells [73,74]. Interestingly, Suv4-20h
has been implicated in the maintenance of genome stability [75] and Suv4-20h double-knockout mice present with
chromosomal aberrations due to less-efficient DNA double-strand break repair [76]. H4K20me3 levels are also
reduced in late-passage cycling human diploid fibroblasts
(HDFs) [52]. Furthermore, exogenous expression of telomerase does not restore H4K20me3 levels, suggesting
that replicative senescence and DNA damage responses
are not responsible for elevation of trimethyl-H4K20 in
HDFs [52]. By contrast, upregulation of H4K20me3 has
been observed in the premature aging disorder HutchinsonGilford Progeria Syndrome [77] and in the livers and
kidneys of elderly rats [78]. Of note, in contrast to senescent fibroblasts derived by extensive passaging [52],
H4K20me3 levels were found to be elevated in RAS-induced senescent cells [79], suggesting differences in senescence states depending on how senescence is induced
[15].
Other aging-associated histone modifications include
H3K9 acetylation and trimethylation of H3K4, H3K9,
and H3K27. Changes in these modifications have been
observed in cancers, although their levels vary depending
on tumor type (Table 1). For example, breast cancer cells
show low H3K9ac levels [80], whereas lung cancer cells
show high levels [81]. An increase in H3K9ac, the substrate for the histone deacetylase (HDAC) Sirt6 [82],
which increases longevity in mammals, occurs in aged
cycling human fibroblasts in vitro [52]. Mice deficient in
SIRT6 exhibit accelerated aging [83], whereas transgenic
mice overexpressing SIRT6 have a longer lifespan
than control animals [84]. These findings are interesting
given that much evidence points to a role of SIRT6 as a
tumor suppressor, particularly via its role in DNA repair
and genomic stability. Mouse embryonic fibroblasts
from SIRT6-deficient mice exhibit chromosomal aberrations including fragmented chromosomes and detached
centromeres [83]. Along with H3K9ac levels, SIRT6
levels vary depending on the tumor type. SIRT6 is
downregulated in several human cancers, such as
pancreatic cancer, colorectal cancer, and hepatocellular
carcinoma (HCC) [68], but upregulated in prostate
cancer [85]. It has been suggested that SIRT6 exerts
its longevity function by reducing harmful levels of
H3K9ac [86].
Aged cells are also characterized by increased levels of
H3K4me3, a mark of active chromatin, and a decrease of
H3K9me3, a mark of repressed chromatin [52]. By contrast, H3K9me3 levels are elevated in oncogene-induced
senescent cells and the mark accumulates in compacted
heterochromatin foci [87,88]. H3K9me3 has been associated with both positive and negative patient prognosis in
several cancers depending on tumor type, including acute
myeloid leukemia [89], salivary adenoid cystic carcinoma
[90], and gastric adenocarcinoma [91]. Trimethylation of
4
Review
Long noncoding RNAs (lncRNAs)
Noncoding RNAs have emerged as important regulatory
molecules modulating gene expression [106,107]. Using
tiling arrays and deep sequencing to study gene expression
at a genome-wide scale, it has become clear that the human
genome is pervasively transcribed and transcription is not
limited to protein-coding regions [108110]. In addition to
different types of small noncoding RNA [106], which function via interaction with RNA-binding proteins or mRNA,
the human genome expresses a high number of noncoding
transcripts larger than 200 bp known as lncRNAs, which
play regulatory roles in a wide range of biological processes
[107]. lncRNAs can affect the expression of genes in cis or
trans via association with other RNAs [111,112] or proteins
such as transcription factors, RNA-binding proteins, or
chromatin-modifying enzymes [107].
Numerous lncRNAs have been linked to cancer [113],
many of which associate with chromatin or chromatinmodifying enzymes (Table 1). HOTAIR, which is transcribed from the HOX gene cluster, is overexpressed in a
subset of breast cancers and its expression promotes metastasis and is correlated with poor prognosis [114].
HOTAIR binds to PRC2 and the histone demethylase
LSD1 complex to modulate target gene expression
[114,115]. Another lncRNA generated from the HOX gene
cluster, HOTTIP, is overexpressed in HCC, where its
expression is associated with poor patient survival [116].
Interestingly, HOTTIP acts by inducing gene expression by
interacting with adaptor protein WDR5 of the MLL complex implicated in leukemia [117]. CTBP1-AS is an androgen-responsive lncRNA that is overexpressed in prostate
cancer, where it exerts tumor-suppressive effects by inhibiting the expression of its antisense gene CTBP1, a corepressor for the androgen receptor [118]. CTBP1-AS binds
to the HDACmSin3A complex to decrease histone H3
acetylation and H3K4 methylation levels at the CTBP1
promoter [118]. The lncRNA ANRASSF1 is overexpressed
in breast and prostate cells and inhibits the tumor-suppressor gene RASSF1A [119] by forming an RNA/DNA
hybrid that recruits the silencing complex PRC2 to the
RASSF1A gene promoter [119]. Deletion of XIST, the
prototypical lncRNA which mediates X chromosome inactivation and female dose compensation by interacting with
PRC2 [120], in the blood compartment of mice results in
genome instability and female-specific, fully penetrant
lethal blood cancer [121], suggesting a tumor-protective
role for XIST. It is generally unclear whether the observed
changes in lncRNAs and the associated changes in gene
expression are the drivers or consequences of cancer.
Early observations also indicate the relevance of
lncRNAs in aged cells and tissues. It has been noticed that
young and senescent cells show differential expression of
several lncRNAs [122]. The expression of some lncRNAs,
such as MALAT1, XIST, and MIAT, is lower in cells
undergoing senescence and knock down of MALAT1 and
MIAT in early-passage fibroblasts induces senescence
[122]. One such lncRNA, SAL-RNA1, which is downregulated in senescent cells, is thought to delay senescence as
its knock-down promotes phenotypic traits of senescence,
including enlarged cell size and positive b-galactosidase
staining, possibly via modulating p53 levels [122]. Further
Review
DNA
methylaon
Gene mis-regulaon
Histone
modicaons
Mutaons
ncRNAs
Altered global chroman landscape
Young
Tumor suppressor
and oncogene acvity
Transformaon
pre-disposion
Cancer
cell
Old
Aging
Environmental inuences
- Pollutants
- Irradiaon
- Diet
Intrinsic events
- Genome instability
- Gene expression changes
Figure 2. Chromatin-based mechanism of aging-associated tumorigenesis. Aging is accompanied by global and local changes in DNA methylation, histone modifications,
and noncoding RNA (ncRNA) expression brought about by intrinsic and environmental factors. Aging-associated changes in chromatin may promote tumorigenesis by
silencing tumor suppressors or activating oncogenes, altering the global chromatin landscape and chromatin organization, or increasing DNA damage.
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