cancer as a dysregulated epigenome
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7/27/2019 Cancer as a Dysregulated Epigenome
Even before the discovery of epigenetic mod-ifications in cancer, classical tumour biologysuggested that generalized disruption of geneexpression might underlie the key proper-ties of unregulated tumour growth, invasionand metastasis. Perhaps the earliest personto recognize the importance of gene expres-sion in cancer was Sidney Weinhouse, whodescribed a generalized disruption of the
biochemistry of cancer cells that was focusedon isozymes that were primarily related tometabolism1. However, since the discovery ofoncogene mutation in human tumours2, theprincipal focus of cancer genetics has beenon mutations. We argue in this Opinion arti-cle that, although key mutational changes arenecessary for the initiation of what we cur-rently recognize as neoplastic growth and arelikely to be required for escape from a cellularniche, epigenetic modifications also have acrucial role: these modifications allow rapidcellular selection in a changing environment,
thus leading to a growth advantage for thetumour cells at the expense of the host. This
view does not contradict and indeed col-laborates with the genetic model, but it putsepigenetics at the very heart of cancer biol-ogy, from normal precursor cells at the siteswhere cancer arises, and through all stages oftumour progression, to advanced metastaticdisease.
The first experiments on DNA methy-lation in human cancer, which comparedsamples of human colorectal cancer withmatched normal mucosa isolated fromthe same patients, showed widespreadhypomethylation involving approximatelyone-third of single-copy genes3. In responseto the discovery of tumour suppressorgenes4, later studies focused on identifyingsilenced genes as surrogates for mutation,beginning with the observation of promoterhypermethylation ofRB1 by Horsthemkeand colleagues5,6. During the 2000s, the
maturation of microarrays and the adventof next-generation sequencing technologiesin combination with the rise of data-drivendiscovery in biology have led to importantnew insights. These include the discoveryof genome-wide loss of epigenetic stability,which is common across disparate tumourtypes. This seems to be the underlying mech-anism for both the hypomethylation and thehypermethylation of individual genes, whichwas the historical focus of this field7. In addi-tion, recently discovered mutations in theepigenetic apparatus probably contribute
to epigenetic disruption in cancer. We reviewthese recent discoveries and point to thepossibility that cancer is a state in which theepigenome is allowed to have greater plas-ticity than it is supposed to have in normalsomatic tissues. This increased epigeneticplasticity is a normal component of develop-ment or postnatal responses to injury, but itsconstitutive activation in cancer causes epige-netic heterogeneity that leads to most of theclassical cancer hallmarks. We discuss belowhow this perspective provides new researchavenues for diagnostics and treatment.
Large epigenetic structures
Just as the field of cancer epigenetics waspresaged by early studies of abnormal geneexpression, the role of large epigeneticstructures in cancer was indicated by theearliest studies of cancer epigenetics byTheodor Boveri, who described abnormalchromatin in cancer cells in photomicro-graphs in 1929 (REF. 8). Alterations in nuclearshape are often used for diagnosis and arepotentially symptomatic of the disorganiza-tion of this carefully regulated state9. In addi-tion, nuclear lamina proteins (which serve
to retain nuclear organization) show alteredgene expression in cancer10. We describebelow advances from whole-genome ana-lyses that begin to provide molecular detailto these altered structures in cancer.
Chromatin LOCKs and LADs.Euchromatinrefers to genes that are more open to tran-scription owing to post-translational modi-fications of histones and lower nucleosomedensity, whereas heterochromatin is the oppo-site: genes that are less open to transcriptionowing to greater nucleosome density and
E P I G E N E T I C S A N D G E N E T I C S O P I N I O N
Cancer as a dysregulated epigenomeallowing cellular growth advantageat the expense of the host
Winston Timp and Andrew P. Feinberg
Abstract | Although at the genetic level cancer is caused by diverse mutations,
epigenetic modifications are characteristic of all cancers, from apparently normalprecursor tissue to advanced metastatic disease, and these epigenetic
modifications drive tumour cell heterogeneity. We propose a unifying model of
cancer in which epigenetic dysregulation allows rapid selection for tumour cell
survival at the expense of the host. Mechanisms involve both genetic mutations
and epigenetic modifications that disrupt the function of genes that regulate the
epigenome itself. Several exciting recent discoveries also point to a genome-scale
disruption of the epigenome that involves large blocks of DNA hypomethylation,
mutations of epigenetic modifier genes and alterations of heterochromatin in
cancer (including large organized chromatin lysine modifications (LOCKs) and
lamin-associated domains (LADs)), all of which increase epigenetic and gene
expression plasticity. Our model suggests a new approach to cancer diagnosis and
therapy that focuses on epigenetic dysregulation and has great potential for risk
detection and chemoprevention.
NATURE REVIEWS |CANCER ADVANCE ONLINE PUBLICATION |1
Nature Reviews Cancer| AOP, published online 13 June 2013; doi:10.1038/nrc3486
2013 Macmillan Publishers Limited. All rights reserved
7/27/2019 Cancer as a Dysregulated Epigenome
certain post-translational histone modifica-tions. Typically, facultative heterochromatin that is, a region that can switch betweentranscriptionally repressive states and acti-
vated states is examined at a local genelevel. However, in addition to small-scalechanges, the genome is partitioned into largeeuchromatic and heterochromatic domains,which have been given different names formostly overlapping structures by laborato-ries that have approached this organizationusing varying methods. We recently reportedlarge organized chromatin lysine modifications(LOCKs), which are defined by genomicdomains enriched for heterochromatin post-translational modifications, such as histoneH3 lysine 9 dimethylation (H3K9me2)11.LOCKs expand during differentiation and arelost in cancer11(FIG. 1a,b). Heterochromaticregions can also be defined by their organiza-tion and position within the nucleus: DNA
sequences associated with proteins in thenuclear lamina are known as lamina-associateddomains (LADs)12. Heterochromatic regionsdefined by histone modifications (LOCKs)and those defined by nuclear location (LADs)have been shown to have 80% overlap in dif-ferent samples11,13,14, but a causal relationship,as in LADs controlling chromatin or chro-matin informing nuclear location, has not yetbeen proved.
LOCKs and LADs change during develop-ment, generally increasing in size. Genesin LADs are typically transcriptionallyrepressed15, but by artificially reorganizingthe nucleus to move genes to the nuclearperiphery, transcription profiles and his-tone modifications of chromatin contain-ing these genes are drastically altered15.Genes encoding proteins that are involvedin organizing the nuclear membrane alsohave altered expression in many differentcancer types16. Different laboratories haveobserved dynamic changes in chromatinstate by examining different histone sites for example, H3K9me2, H3K9 trimethyla-tion (H3K9me3) or H3K27me3 but stillnote that the prevalence of heterochromatic
regions is associated with the differentiationstate of the cell17,18. LOCKs are also alteredin cells undergoing epithelialmesenchymaltransition (EMT), an important behaviour incancer progression: during EMT, chromatinis reprogrammed in bulk, which results in adramatic loss of H3K9me2 and an increaseof H3K4me3 and H3K36me3 (REF. 19).Chromatin immunoprecipitation followed bymicroarray (ChIPchip) experiments carriedout on mouse chromosomes 414 showedloss of H3K9me2 in 96% of LOCKs but notin non-LOCK regions19.
The study of LOCKs and LADs in canceris very new, and even chromatin modifica-tions that are known targets of mutations,such as H3K27me3, have not yet beenanalysed systematically at a genome-scalesequencing level in cancer. A great deal ofdetail and mechanism needs to be fleshedout. For example, LOCKs and LADs maythemselves be nuanced with regard to com-binations of chromatin marks that definephysiologically distinct domains20. To date,other than pilot studies, there has beenno systematic analysis of primary humancancers and matched normal tissues withrespect to LOCKs and LADs. More detailedstudy has been carried out on blocks of DNAmethylation (discussed below), but theseneed to be related to LOCKs and LADs toform a complete picture of large-scale epi-genetic alterations in cancer. Euchromatinislands provide a clue to a possible connection
between LOCKs and LADs; these islands aresmall regions within the larger LOCKs andLADs that have reduced amounts of hetero-chromatin and are enriched for DNase hyper-sensitive sites and differentially methylatedregions in cancer21.
Hypomethylated blocks. We recently made asurprising discovery by using whole-genomebisulphite sequencing of human colorectalcancer samples, and this finding helps toexplain the earliest observation in cancerepigenetics: the widespread hypomethylationof genes in cancer3. By comparing three sam-ples of colorectal cancer to matched normalmucosa from the same patients, we identifiedlong blocks of hypomethylated DNA in can-cer with a median size of 28 kb and a maxi-mum size of 10 Mb (a range of 5 kb10 Mb)7(FIG. 1a,b