Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Histone Modifications and Cancer James E. Audia1 and Robert M. Campbell2 1Constellation Pharmaceuticals, Cambridge, Massachusetts 02142; 2Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285 Correspondence: [email protected] SUMMARY Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable maintenance of repressive chromatin. In this article, we review many of the key and newly identified histone modifi- cations known to be deregulated in cancer and how this impacts function. The latter part of the article addresses the challenges and current status of the epigenetic drug development process as it applies to cancer therapeutics. Outline 1 Introduction 3 Drug-discovery challenges for histone- modifying targets 2 Histone modifications References Editors: C. David Allis, Marie-Laure Caparros, Thomas Jenuwein, Danny Reinberg, and Monika Lachner Additional Perspectives on Epigenetics available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a019521 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a019521 1 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press J.E. Audia and R.M. Campbell OVERVIEW Cancer is a diverse collection of diseases characterized by the Collectively, the combination of histone marks found in dysregulation of important pathways that control normal cel- a localized region of chromatin function through multiple lular homeostasis. This escape from normal control mecha- mechanisms as part of a “chromatin-based signaling” system nisms leads to the six hallmarks of cancer, which include (Jenuwein and Allis 2001; Schreiber and Bradley 2002). The sustaining proliferative signaling, evading growth suppres- landscape of known histone and nonhistone modifications sors, resisting cell death, enabling replicative immortality, in- that affect chromatin-based processes continues to expand. ducing angiogenesis, and activating invasion and metastasis The diverse set of observed histone adornments includes (Hanahan and Weinberg 2011). The systematic investigation phosphorylation, citrullination, sumoylation, adenosine di- of the acquired and inherited molecular alterations in the phosphate (ADP) ribosylation, deimination, and crotonyla- genomes of somatic cells has revealed a great deal about tion. The various known epigenetic mechanisms work in a the genetic basis for cancer initiation, progression, and main- concerted and interdependent fashion to regulate gene tenance. This progress has afforded a number of promising expression. In cancers, their misregulation can result in the and effective opportunities for therapeutic intervention. inappropriate activation of oncogenes or, conversely, the in- The epigenetic mechanisms that govern transcriptional appropriate inactivation of tumor suppressors. There is also a regulation and the corresponding dysregulation in cancer, growing understanding and appreciation for the genetic basis initially less well studied, have increasingly become the focus contributing to epigenetic changes observed in cancer. This of cancer researchers, although the transgenerational effects adds to the complexity of cancer etiology and, perhaps, offers remain largely unexplored. “Epigenetic” transcriptional con- important general insights into the epigenetic basis of human trol can occur through DNA methylation, covalent histone disease. modification, the reading of these modifications by protein This article speaks of some of the challenges faced by recognition modules, histone exchange, and alteration by the epigenetic drug discovery process, searching for mole- ATP-dependent chromatin remodelers and via the effects of cules targeting epigenetic regulators and also supporting noncoding RNA. Because DNA methylation in cancer is an emerging role of epigenetic alterations that occur during addressed elsewhere, this article focuses on many of the chemotherapy, thought to contribute to drug resistance. covalent histone modifications that are altered in cancer, Finally, it highlights some of the more recent progress particularly the well-studied acetylation and methylation toward developing therapeutic agents in this promising target modifications. space. 2 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a019521 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Histone Modifications and Cancer 1 INTRODUCTION coupled to chromatin immunoprecipitation) technology. These findings have come on the back of the earlier, more DNA within cells is packaged as chromatin, a dynamic established findings linking aberrant DNA methylation to structure composed of nucleosomes as the fundamental cancer, discovered in the early 1980s (see Baylin and Jones building blocks. Histones are the central component of 2014). In addition to recent PTM mapping projects, se- the nucleosomal subunit, forming an octamer containing quencing efforts have also now identified many of the en- the four core histone proteins (H3, H4, H2A, H2B) around zymes responsible for placing (“writers”) and removing which is wrapped a 147-base-pair segment of DNA. Each (“erasers”) such epigenetic marks (Fig. 1). Mutations in of the largely globular histone proteins possesses a charac- such enzymes turn out to be among the most frequently teristic side chain, or tail, which is densely populated with mutated targets in cancers (Shen and Laird 2013). Collec- basic lysine and arginine residues. The histone tails are tively, these findings show interplay between cancer genet- subject to extensive covalent posttranslational modifica- ics and epigenetics, adding to the complexity in our tions (PTMs) that cooperate to govern the chromatin state. understanding of the oncogenic process. Advances in Some PTMs can alter the charge density between histones whole genome/exome sequencing of patient tumors have and DNA, impacting chromatin organization and under- allowed for the identification of possible key epigenetic lying transcriptional processes, but they can also serve as drivers of cancer. These epigenetic drivers may silence recognition modules for specific binding proteins that, one or more tumor-suppressor genes and/or activate when bound, may then signal for alterations in chromatin oncogenes, thus providing an alternative mechanism by structure or function. which oncogenic reprogramming of the genome may occur Alterations in the patterns of histone PTMs have been (Shen and Laird 2013). Genomic studies have clearly im- extensively linked to cancer, both at the global level across plicated dysregulation of chromatin modifiers as drivers the genome (Seligson et al. 2005; Bannister and Kouzarides in many types of cancer (Garraway and Lander 2013) and 2011) and at specific gene loci, using ChIP-chip (chromatin recurrent mutations occur in the genes that encode the immunoprecipitation with DNA microarray analysis) enzymes, which add, remove, and interpret the covalent and ChIP-sequencing (parallel sequencing technologies histone modifications. Intriguingly, certain chromatin ENHANCER PROMOTER GENE BODY WRITERS ERASERS READERS H3 tail Me Me1 Me Me MLL1-5 KDM1A/B MLL,CHD1,BPTF,RAG2 K4 Me3 Me SETD1A/D KDM5A/B/C ING,KDM5,TAF3 Me Me3 Me Me SUV39H1/2 KDM3/4 HP1,ATRX K9 Ac Ac CBP/P300 HDACs/SIRTs BRD4 Me EZH2,EZH1 Me1 Me Me KDM6A/B EED,PC K27 Ac Ac CBP/P300 HDACs/SIRTs BRD4 Me K36 Me3 Me Me SETD2 KDM4 ZYMNDII PHF19 K79 Me2 Me Me DOT1L ? ? Figure 1. Histone writers, erasers, and readers in cancer. Histone H3 tail lysine residues, frequently subject to posttranslational modifications (PTMs), are indicated along the left side. The typical distribution of these H3 PTMs is also indicated along the length of gene loci (including distal enhancers) as shaded blocks. Green (meth- ylation) or cyan (acetylation) indicates histone marks associated with active genes, whereas red shading is indicative of silent genes. A few examples of writers, erasers, and readers that may propagate a mark or act as an effector protein are listed on the right side of the figure. For a more complete listing of these proteins, see Appendices A–D at the end of this article. Cite this article as Cold Spring Harb Perspect Biol 2016;8:a019521 3 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press J.E. Audia and R.M. Campbell modifiers have been identified in cancer, for both increased may also be modified in other ways, some of which are and decreased levels of functionality, suggesting they oper- illustrated in Figure 6 of Allis et al. (2014) or included in ate both as tumor-suppressor genes and oncogenes. The Zhao and Garcia (2014). These include citrullination, ubiq- loss-of-function mutations in affected tumors are often uitination, ADP-ribosylation, deamination, formylation, heterozygous, suggesting that haploinsufficiency for these O-GlcNAcylation, propionylation, butyrylation, crotony- chromatin-modifying enzymes drives the cancer, whereas lation, and proline isomerization (Chen et al. 2007; Martin total absence of function is cell lethal. As a result, this and Zhang 2007; Ruthenburg et al. 2007; Tan et al. 2011; class of