Oncogene (2011) 30, 3391–3403 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW Histone onco-modifications JFu¨llgrabe, E Kavanagh and B Joseph Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden Post-translational modification of histones provides an (Luger et al., 1997). In eukaryotes, an octamer of important regulatory platform for processes such as gene histones-2 copies of each of the four core histone expression, DNA replication and repair, chromosome proteins histone 2A (H2A), histone 2B (H2B), histone condensation and segregation and apoptosis. Disruption of 3 (H3) and H4—is wrapped by 147 bp of DNA to form these processes has been linked to the multistep process of a nucleosome, the fundamental unit of chromatin carcinogenesis. We review the aberrant covalent histone (Kornberg and Lorch, 1999). Nucleosomal arrays were modifications observed in cancer, and discuss how these observed with electron microscopy as a series of ‘beads epigenetic changes, caused by alterations in histone- on a string’, the ‘beads’ being the individual nucleo- modifying enzymes, can contribute to the development of somes and the ‘string’ being the linker DNA. Linker a variety of human cancers. As a conclusion, a new histones, such as histone H1, and other non-histone terminology ‘histone onco-modifications’ is proposed to proteins can interact with the nucleosomal arrays to describe post-translational modifications of histones, further package the nucleosomes to form higher-order which have been linked to cancer. This new term would chromatin structures (Figure 1a). take into account the active contribution and importance Histones are no longer considered to be simple ‘DNA- of these histone modifications in the development and packaging’ proteins; they are recognized as being progression of cancer. regulators of chromatin dynamics. Histones are subject Oncogene (2011) 30, 3391–3403; doi:10.1038/onc.2011.121; to a wide variety of post-translational modifications published online 25 April 2011 including acetylation of lysines and methylation of lysines and arginines as well as serine and threonine Keywords: histone modification; histone-modifying phosphorylation, lysine ubiquitylation, glycosylation, enzymes; carcinogenesis; acetylation; methylation sumoylation, adenosine diphosphate ribosylation and carbonylation, all of which are carried out by histone- modifying enzyme complexes in a dynamic manner (Khorasanizadeh, 2004). These modifications occur Introduction primarily within the histone amino-terminal tails pro- truding from the surface of the nucleosome as well as on The initiation and progression of cancer, traditionally the globular core region (Cosgrove et al., 2004). Histone seen as a genetic disease, is now realized to involve modifications are proposed to affect chromosome epigenetic abnormalities along with genetic alterations. function through at least two distinct mechanisms. The Epigenetics is defined as stably heritable changes in gene first mechanism suggests that modifications may alter expression that are not due to any alteration in the DNA the electrostatic charge of the histone resulting in a sequence (Berger et al., 2009). The study of epigenetic structural change in histones or their binding to DNA. mechanisms in cancer, such as DNA methylation, The second mechanism proposes that these modifica- histone modifications, microRNA expression and nu- tions are binding sites for protein recognition modules, cleosome positioning has revealed a plethora of events such as the bromodomains or chromodomains, which that contribute to the neoplastic phenotype. In this recognize acetylated lysines or methylated lysines, review, we summarize the current state of knowledge respectively. regarding the status of histone modifications and For each post-translational modification of histones, associated histone-modifying enzymes in cancer cells. enzymes exist which either lay down the appropriate We discuss how covalent histone modifications can be mark or remove it. Major factors in this regulation are associated with cancer initiation and progression. the histone acetyltransferases, which acetylate the Histones are the chief protein components of chro- histone tails and induce chromatin decondensation; matin, acting as spools around which DNA winds histone deacetylases (HDACs), which remove the acetyl groups and promote a tighter binding of histones to DNA; histone methyltransferases (HMTs), which pro- Correspondence: Dr B Joseph, Department of Oncology-Pathology, mote or inhibit transcription depending on the target Karolinska Institutet, Cancer Centrum Karolinska, R8:03, Stockholm- histone residue; and histone demethylases (HDMs), 171 76, Sweden. E-mail: [email protected] which counteract the HMTs (Allis et al., 2007; Fullgrabe Received 20 February 2011; revised and accepted 11 March 2011; et al., 2010). The histone-modifying enzymes affect published online 25 April 2011 histones either locally, through targeted recruitment by Histone onco-modifications JFu¨llgrabe et al 3392 histone tail Linker DNA H1 H1 DNA H2B H2A H2B H2A H4 H3 H4 H3 octameric histone core histone nucleosome posttranslational modifications Ac AcAc Ac Me SGRGK GGK GLGK GGAK RHRK VL H4NH2 - 5 8 12 16 20 Me Me Me Ac Ac K 56 ARTK QTARK STGGKAPRK QLATKAARK SA H3NH2 - 4 9 18 27 Ac Me Ac gain Me Ac loss Figure 1 Chromatin structure and histone onco-modifications. (a) Chromatin is made of repeating units of nucleosomes, which consist of B147 base pairs of DNA wrapped around a histone octamer consisting of two copies each of the core histones H2A, H2B, H3 and H4. Linker histone H1 is positioned on top of the nucleosome core particules stabilizing higher order chromatin structure. The histones are subject to a wide variety of post-translational modifications, primarily on their N-terminal tails, but also in their globular core region. (b) Histone onco-modifications; post-translation modifications on histone tails that occur in cancer cells are represented. The modifications shown are discussed in the main text, apart from H4K5ac and H4K8ac (Van Den Broeck et al., 2008). ac, acetylated; me, methylated. sequence-specific transcription factors (Rundlett et al., have important and tumor-specific roles in cancer 1998), or globally throughout the genome in an development. untargeted manner affecting virtually all nucleosomes (Vogelauer et al., 2000). Such widespread functions that occur independently of apparent sequence-specific DNA-binding proteins are referred to as global histone Histone code hypothesis modifications. Similar to their targeted effects, the global activity of the histone-modifying enzymes can Work on histone modifications and regulation of gene also modulate gene activity (Vogelauer et al., 2000). expression have coalesced into the ‘histone code’ Therefore, histones are modified locally and globally hypothesis, initially proposed by Strahl and Allis (2000) through multiple histone-modifying enzymes with dif- and Turner (2000), that encapsulates the function of ferent substrate specificities, generating hierarchical histone modifications in chromatin structure and in the patterns of modifications from single promoters to large regulation of nuclear functions. According to the histone regions of chromosomes and even single cells. At last, code hypothesis, distinct combinations of covalent post- growing evidence suggests that histone-modifying translational modifications of histones influence chroma- enzymes are found deregulated in human cancers. In tin structure and lead to varied transcriptional outputs fact, an extensive analysis of expression patterns of (Strahl and Allis, 2000). The concept was further histone-modifying enzymes was even able to discrimi- generalized to the idea that various combinations of nate between tumor samples and their normal counter- histone modifications are related to specific chromatin- parts and cluster the tumor samples according to related functions and processes (Jenuwein and Allis, cell type (Ozdag et al., 2006). This indicates that 2001). As an example, several histone modifications have changes in the expression of histone-modifying enzymes been firmly linked to apoptosis-induced chromatin Oncogene Histone onco-modifications JFu¨llgrabe et al 3393 changes, providing collective evidence for an ‘apoptotic modifications during gene silencing, an increasing histone code’ (Fullgrabe et al.,2010). number of studies argue that DNA methylation takes its cue primarily from histone modification states (Cedar and Bergman, 2009). Thus, a complex Away from DNA methylation; closer to histone picture is emerging in which an epigenetic cross-talk, the modification interplay between DNA methylation and histone modification, is involved in the process of gene DNA methylation is probably the most intensely studied transcription and aberrant gene silencing in tumors epigenetic modification and aberrant changes in DNA (Vaissiere et al., 2008). methylation (global hypomethylation and CpG island hypermethylation) were among the first events to be recognized in cancer. A link between DNA methylation Histone onco-modifications and alterations of the histone and cancer was established in 1983, when Feinberg and modifying enzymatic system in cancer Vogelstein (1983) demonstrated that the genomes of cancer cells are hypomethylated relative to their normal Overall, post-translational modifications of histones counterparts. Global demethylation in the repetitive create an epigenetic mechanism for