Cancer Epigenetics: from Mechanism to Therapy
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Leading Edge Review Cancer Epigenetics: From Mechanism to Therapy Mark A. Dawson1,2 and Tony Kouzarides1,* 1Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK 2Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke’s Hospital, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2012.06.013 The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated target- ing regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggest- ing that their misregulation can culminate in cancer. This information, along with the promising clin- ical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer. Chromatin is the macromolecular complex of DNA and histone The information conveyed by epigenetic modifications plays proteins, which provides the scaffold for the packaging of our a critical role in the regulation of all DNA-based processes, entire genome. It contains the heritable material of eukaryotic such as transcription, DNA repair, and replication. Conse- cells. The basic functional unit of chromatin is the nucleosome. quently, abnormal expression patterns or genomic alterations It contains 147 base pairs of DNA, which is wrapped around in chromatin regulators can have profound results and can a histone octamer, with two each of histones H2A, H2B, H3, lead to the induction and maintenance of various cancers. In and H4. In general and simple terms, chromatin can be subdi- this Review, we highlight recent advances in our understanding vided into two major regions: (1) heterochromatin, which is of these epigenetic pathways and discuss their role in oncogen- highly condensed, late to replicate, and primarily contains inac- esis. We provide a comprehensive list of all the recurrent cancer tive genes; and (2) euchromatin, which is relatively open and mutations described thus far in epigenetic pathways regulating contains most of the active genes. Efforts to study the coordi- modifications of DNA (Figure 2), histones (Figures 3, 4, and 5), nated regulation of the nucleosome have demonstrated that all and chromatin remodeling (Figure 6). Where relevant, we will of its components are subject to covalent modification, which also emphasize existing and emerging drug therapies aimed at fundamentally alters the organization and function of these basic targeting epigenetic regulators (Figure 1). tenants of chromatin (Allis et al., 2007). The term ‘‘epigenetics’’ was originally coined by Conrad Wad- Characterizing the Epigenome dington to describe heritable changes in a cellular phenotype Our appreciation of epigenetic complexity and plasticity has that were independent of alterations in the DNA sequence. dramatically increased over the last few years following the Despite decades of debate and research, a consensus definition development of several global proteomic and genomic technol- of epigenetics remains both contentious and ambiguous (Berger ogies. The coupling of next-generation sequencing (NGS) plat- et al., 2009). Epigenetics is most commonly used to describe forms with established chromatin techniques such as chromatin chromatin-based events that regulate DNA-templated pro- immunoprecipitation (ChIP-Seq) has presented us with a previ- cesses, and this will be the definition we use in this review. ously unparalleled view of the epigenome (Park, 2009). These Modifications to DNA and histones are dynamically laid technologies have provided comprehensive maps of nucleo- down and removed by chromatin-modifying enzymes in a highly some positioning (Segal and Widom, 2009), chromatin confor- regulated manner. There are now at least four different DNA mation (de Wit and de Laat, 2012), transcription factor binding modifications (Baylin and Jones, 2011; Wu and Zhang, 2011) sites (Farnham, 2009), and the localization of histone (Rando and 16 classes of histone modifications (Kouzarides, 2007; Tan and Chang, 2009) and DNA (Laird, 2010) modifications. In addi- et al., 2011). These are described in Table 1. These modifications tion, NGS has revealed surprising facts about the mammalian can alter chromatin structure by altering noncovalent interac- transcriptome. We now have a greater appreciation of the fact tions within and between nucleosomes. They also serve as that most of our genome is transcribed and that noncoding docking sites for specialized proteins with unique domains that RNA may play a fundamental role in epigenetic regulation (Ama- specifically recognize these modifications. These chromatin ral et al., 2008). readers recruit additional chromatin modifiers and remodeling Most of the complexity surrounding the epigenome comes enzymes, which serve as the effectors of the modification. from the modification pathways that have been identified. 12 Cell 150, July 6, 2012 ª2012 Elsevier Inc. Table 1. Chromatin Modifications, Readers, and Their Function Chromatin Modification Nomenclature Chromatin-Reader Motif Attributed Function DNA Modifications 5-methylcytosine 5mC MBD domain transcription 5-hydroxymethylcytosine 5hmC unknown transcription 5-formylcytosine 5fC unknown unknown 5-carboxylcytosine 5caC unknown unknown Histone Modifications Acetylation K-ac BromodomainTandem, transcription, repair, replication, PHD fingers and condensation Methylation (lysine) K-me1, K-me2, K-me3 Chromodomain, Tudor domain, transcription and repair MBT domain, PWWP domain, PHD fingers, WD40/b propeller Methylation (arginine) R-me1, R-me2s, R-me2a Tudor domain transcription Phosphorylation S-ph, T-ph 14-3-3, BRCT transcription, repair, (serine and threonine) and condensation Phosphorylation (tyrosine) Y-ph SH2a transcription and repair Ubiquitylation K-ub UIM, IUIM transcription and repair Sumoylation K-su SIMa transcription and repair ADP ribosylation E-ar Macro domain, PBZ domain transcription and repair Deimination R/Cit unknown transcription and decondensation Proline isomerisation P-cis5P-trans unknown transcription Crotonylation K-cr unknown transcription Propionylation K-pr unknown unknown Butyrylation K-bu unknown unknown Formylation K-fo unknown unknown Hyroxylation Y-oh unknown unknown O-GlcNAcylation S-GlcNAc; T-GlcNAc unknown transcription (serine and threonine) Modifications: me1, monomethylation; me2, dimethylation; me3, trimethylation; me2s, symmetrical dimethylation; me2a, asymmetrical dimethylation; and Cit, citrulline. Reader domains: MBD, methyl-CpG-binding domain; PHD, plant homeodomain; MBT, malignant brain tumor domain; PWWP, proline-tryptophan-tryptophan-proline domain; BRCT, BRCA1 C terminus domain; UIM, ubiquitin interaction motif; IUIM, inverted ubiquitin interaction motif; SIM, sumo interaction motif; and PBZ, poly ADP-ribose binding zinc finger. aThese are established binding modules for the posttranslational modification; however, binding to modified histones has not been firmly established. Recent improvements in the sensitivity and accuracy of mass et al., 2010; Ruthenburg et al., 2011). The latter approach in spectrometry (MS) instruments have driven many of these particular has uncovered some of the rules governing the recruit- discoveries (Stunnenberg and Vermeulen, 2011). Moreover, ment of protein complexes to methylated DNA and modified although MS is inherently not quantitative, recent advances in histones in a nucleosomal context. The next step in our under- labeling methodologies, such as stable isotope labeling by standing will require a high-resolution in vivo genomic approach amino acids in cell culture (SILAC), isobaric tags for relative to detail the dynamic events on any given nucleosome during the and absolute quantification (iTRAQ), and isotope-coded affinity course of gene expression. tag (ICAT), have allowed a greater ability to provide quantitative measurements (Stunnenberg and Vermeulen, 2011). Epigenetics and the Cancer Connection These quantitative methods have generated ‘‘protein recruit- The earliest indications of an epigenetic link to cancer were ment maps’’ for histone and DNA modifications, which contain derived from gene expression and DNA methylation studies. proteins that recognize chromatin modifications (Bartke et al., These studies are too numerous to comprehensively detail in 2010; Vermeulen et al., 2010). Many of these chromatin readers this review; however, the reader is referred to an excellent review have more than one reading motif, so it is important to under- detailing the history of cancer epigenetics (Feinberg and Tycko, stand how they recognize several modifications either simulta- 2004). Although many of these initial studies were purely correl- neously or sequentially. The concept of multivalent engagement ative, they did highlight a potential connection between epige- by chromatin-binding modules has recently been explored netic pathways and cancer. These early observations have by using either modified histone peptides (Vermeulen et al., been significantly strengthened by recent results from the Inter- 2010) or in-vitro-assembled and -modified nucleosomes (Bartke national Cancer Genome Consortium (ICGC). Whole-genome Cell 150, July 6, 2012 ª2012 Elsevier Inc. 13 Figure 1. Epigenetic Inhibitors as Cancer