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histone modification


Oncogene (2011) 30, 3391–3403

& 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11
www.nature.com/onc

REVIEW

Histone onco-modi?cations
J Fullgrabe, E Kavanagh and B Joseph ¨
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden

Post-translational modi?cation of histones provides an important regulatory platform for processes such as gene expression, DNA replication and repair, chromosome condensation and segregation and apoptosis. Disruption of these processes has been linked to the multistep process of carcinogenesis. We review the aberrant covalent histone modi?cations observed in cancer, and discuss how these epigenetic changes, caused by alterations in histonemodifying enzymes, can contribute to the development of a variety of human cancers. As a conclusion, a new terminology ‘histone onco-modi?cations’ is proposed to describe post-translational modi?cations of histones, which have been linked to cancer. This new term would take into account the active contribution and importance of these histone modi?cations in the development and progression of cancer. Oncogene (2011) 30, 3391–3403; doi:10.1038/onc.2011.121; published online 25 April 2011 Keywords: histone modi?cation; histone-modifying enzymes; carcinogenesis; acetylation; methylation

Introduction The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Epigenetics is de?ned as stably heritable changes in gene expression that are not due to any alteration in the DNA sequence (Berger et al., 2009). The study of epigenetic mechanisms in cancer, such as DNA methylation, histone modi?cations, microRNA expression and nucleosome positioning has revealed a plethora of events that contribute to the neoplastic phenotype. In this review, we summarize the current state of knowledge regarding the status of histone modi?cations and associated histone-modifying enzymes in cancer cells. We discuss how covalent histone modi?cations can be associated with cancer initiation and progression. Histones are the chief protein components of chromatin, acting as spools around which DNA winds
Correspondence: Dr B Joseph, Department of Oncology-Pathology, Karolinska Institutet, Cancer Centrum Karolinska, R8:03, Stockholm171 76, Sweden. E-mail: Bertrand.joseph@ki.se Received 20 February 2011; revised and accepted 11 March 2011; published online 25 April 2011

(Luger et al., 1997). In eukaryotes, an octamer of histones-2 copies of each of the four core histone proteins histone 2A (H2A), histone 2B (H2B), histone 3 (H3) and H4—is wrapped by 147 bp of DNA to form a nucleosome, the fundamental unit of chromatin (Kornberg and Lorch, 1999). Nucleosomal arrays were observed with electron microscopy as a series of ‘beads on a string’, the ‘beads’ being the individual nucleosomes and the ‘string’ being the linker DNA. Linker histones, such as histone H1, and other non-histone proteins can interact with the nucleosomal arrays to further package the nucleosomes to form higher-order chromatin structures (Figure 1a). Histones are no longer considered to be simple ‘DNApackaging’ proteins; they are recognized as being regulators of chromatin dynamics. Histones are subject to a wide variety of post-translational modi?cations including acetylation of lysines and methylation of lysines and arginines as well as serine and threonine phosphorylation, lysine ubiquitylation, glycosylation, sumoylation, adenosine diphosphate ribosylation and carbonylation, all of which are carried out by histonemodifying enzyme complexes in a dynamic manner (Khorasanizadeh, 2004). These modi?cations occur primarily within the histone amino-terminal tails protruding from the surface of the nucleosome as well as on the globular core region (Cosgrove et al., 2004). Histone modi?cations are proposed to affect chromosome function through at least two distinct mechanisms. The ?rst mechanism suggests that modi?cations may alter the electrostatic charge of the histone resulting in a structural change in histones or their binding to DNA. The second mechanism proposes that these modi?cations are binding sites for protein recognition modules, such as the bromodomains or chromodomains, which recognize acetylated lysines or methylated lysines, respectively. For each post-translational modi?cation of histones, enzymes exist which either lay down the appropriate mark or remove it. Major factors in this regulation are the histone acetyltransferases, which acetylate the histone tails and induce chromatin decondensation; histone deacetylases (HDACs), which remove the acetyl groups and promote a tighter binding of histones to DNA; histone methyltransferases (HMTs), which promote or inhibit transcription depending on the target histone residue; and histone demethylases (HDMs), which counteract the HMTs (Allis et al., 2007; Fullgrabe et al., 2010). The histone-modifying enzymes affect histones either locally, through targeted recruitment by

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histone tail Linker DNA

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Figure 1 Chromatin structure and histone onco-modi?cations. (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 modi?cations, primarily on their N-terminal tails, but also in their globular core region. (b) Histone onco-modi?cations; post-translation modi?cations on histone tails that occur in cancer cells are represented. The modi?cations shown are discussed in the main text, apart from H4K5ac and H4K8ac (Van Den Broeck et al., 2008). ac, acetylated; me, methylated.

sequence-speci?c transcription factors (Rundlett et al., 1998), or globally throughout the genome in an untargeted manner affecting virtually all nucleosomes (Vogelauer et al., 2000). Such widespread functions that occur independently of apparent sequence-speci?c DNA-binding proteins are referred to as global histone modi?cations. Similar to their targeted effects, the global activity of the histone-modifying enzymes can also modulate gene activity (Vogelauer et al., 2000). Therefore, histones are modi?ed locally and globally through multiple histone-modifying enzymes with different substrate speci?cities, generating hierarchical patterns of modi?cations from single promoters to large regions of chromosomes and even single cells. At last, growing evidence suggests that histone-modifying enzymes are found deregulated in human cancers. In fact, an extensive analysis of expression patterns of histone-modifying enzymes was even able to discriminate between tumor samples and their normal counterparts and cluster the tumor samples according to cell type (Ozdag et al., 2006). This indicates that changes in the expression of histone-modifying enzymes
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have important and tumor-speci?c roles in cancer development.

Histone code hypothesis Work on histone modi?cations and regulation of gene expression have coalesced into the ‘histone code’ hypothesis, initially proposed by Strahl and Allis (2000) and Turner (2000), that encapsulates the function of histone modi?cations in chromatin structure and in the regulation of nuclear functions. According to the histone code hypothesis, distinct combinations of covalent posttranslational modi?cations of histones in?uence chromatin structure and lead to varied transcriptional outputs (Strahl and Allis, 2000). The concept was further generalized to the idea that various combinations of histone modi?cations are related to speci?c chromatinrelated functions and processes (Jenuwein and Allis, 2001). As an example, several histone modi?cations have been ?rmly linked to apoptosis-induced chromatin

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changes, providing collective evidence for an ‘apoptotic histone code’ (Fullgrabe et al., 2010).

Away from DNA methylation; closer to histone modi?cation DNA methylation is probably the most intensely studied epigenetic modi?cation and aberrant changes in DNA methylation (global hypomethylation and CpG island hypermethylation) were among the ?rst events to be recognized in cancer. A link between DNA methylation and cancer was established in 1983, when Feinberg and Vogelstein (1983) demonstrated that the genomes of cancer cells are hypomethylated relative to their normal counterparts. Global demethylation in the repetitive regions of the genome early during tumorigenesis might predispose cells to genomic instability and further genetic changes (Robertson, 2005). Aberrant hypermethylation in cancer usually occurs at CpG islands, and the resulting changes in chromatin structure effectively silence transcription. Cancer cells frequently acquire aberrant methylation of multiple tumor-related genes that cooperate to confer a survival advantage to the neoplastic cells (Baylin and Ohm, 2006). Compiling evidence revealed that genes involved in cell-cycle regulation, tumor cell invasion, DNA repair, chromatin remodeling, cell signaling, transcription and apoptosis are aberrantly hypermethylated and silenced in nearly every tumor. DNA methyltransferases are responsible for establishing and maintenance of DNA methylation patterns, which bring stable long-term gene repression. However, it has recently become evident that DNA methylation and histone modi?cation pathways can be dependent on one another, and that this cross-talk can be mediated by biochemical interactions between HMTs and DNA methyltransferases (Tachibana et al., 2008; Cedar and Bergman, 2009; Zhao et al., 2009). Promoter CpG-island hypermethylation in cancer cells is associated to a particular pattern of histone marks including deacetylation of histones H3 and H4, loss of histone H3 lysine trimethylation, and gain of H3K9 methylation and H3K27 trimethylation. Although some studies suggest that DNA methylation patterns guide histone
LSD1 JARID1a JARID1b EZH2 GASC1 G9a

modi?cations during gene silencing, an increasing number of studies argue that DNA methylation takes its cue primarily from histone modi?cation states (Cedar and Bergman, 2009). Thus, a complex picture is emerging in which an epigenetic cross-talk, the interplay between DNA methylation and histone modi?cation, is involved in the process of gene transcription and aberrant gene silencing in tumors (Vaissiere et al., 2008).

Histone onco-modi?cations and alterations of the histone modifying enzymatic system in cancer Overall, post-translational modi?cations of histones create an epigenetic mechanism for the regulation of a variety of normal and disease-related processes. Thus considering the fundamental roles of histone modi?cations, it is not surprising that aberrations in histone modi?cations are discovered in cancer (Sharma et al., 2010) (Figure 1b). However, only a few of the more than 60 residues of histones in which modi?cations have been described have been linked to cancer until now (Kouzarides, 2007). In addition, several of the histonemodifying enzymes have also been described to be altered in cancer cells (Figure 2).

Acetylation of H4K16 Global loss of acetylation of histone H4 at lysine 16 (H4K16Ac), together with loss of trimethylation of histone H4 at lysine 20 (H4K20me3) has been observed along with DNA hypomethylation at repetitive DNA sequences in various primary tumors and were the ?rst histone marks reported deregulated in cancer cells (Fraga et al., 2005). Unlike most histone modi?cations, H4K16ac is unique for regulating higher-order chromatin structures beyond the level of nucleosomes. Indeed, this single histone modi?cation in?uences functional interactions between histones and the chromatin ?ber, providing a potential mechanism to regulate chromatin folding (Shogren-Knaak et al., 2006; Shogren-Knaak and Peterson, 2006). Loss of this mark leads to a more

MLL SMYD3

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Figure 2 Histone-modifying enzymes deregulated in cancer. Several histone-modifying enzymes have been shown to be deregulated in cancer cells. Enzymes for the respective histone onco-modi?cations are represented in green when found to be upregulated or in red if reported as downregulated in cancer cells. Fusion proteins found in cancer cells are depicted in black.
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‘relaxed’ chromatin conformation, which might contribute to genome instability. By now, loss of H4K16ac has been reported for several cancer types and was shown to in?uence cancer cell sensitivity to chemotherapy (Elsheikh et al., 2009; Fraga et al., 2005; Hajji et al., 2010). Reduction in H4K16ac correlates with tumor progression (Fraga et al., 2005). hMOF (human orthologue of the Drosophila melanogaster males absent on the ?rst gene) is the major enzyme that acetylates H4K16 (Neal et al., 2000). Unlike most histone acetyltransferases that target multiple sites on histones, hMOF activity is restricted to residue 16 on the histone H4 tail (Taipale et al., 2005; Utley and Cote, 2003). Worth a notice, hMOF expression is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes for the latter a biomarker for clinical outcome (P?ster et al., 2008). hMOF loss of function leads to defects in the cell cycle and genome instability (Taipale et al., 2005). H4K16ac is deacetylated by the NAD-dependent HDAC sirtuin 1 (SIRT1). Increased expression of SIRT1 has been reported in various tumors, and its use as a prognostic indicator has been proposed (Chen et al., 2005; Hida et al., 2007; Huffman et al., 2007). In addition, a gene designated ‘deleted in breast cancer 1’ (DBC1), which encodes a negative regulator of sirtuin 1 (Cha et al., 2009; Jang et al., 2008), also holds signi?cant prognostic value for breast, gastric and lung carcinoma (Cha et al., 2009; Lee et al., 2011).

Di- and trimethylation of H3K4 Di- and trimethylation of histone H3 at lysine 4 (H3K4me2/me3) is associated with transcriptional competence and activation, with the highest levels observed near transcriptional start sites of highly expressed genes (Shi et al., 2004). A decrease of H3K4me2/me3 is observed in a range of neoplastic tissues and may serve as a predictive factor for clinical outcome for some of them (Seligson et al., 2005; Barlesi et al., 2007; Elsheikh et al., 2009; Ellinger et al., 2010; Manuyakorn et al., 2010; Rajendran et al., 2011). In particular, tumor recurrence occurs earlier in low-grade prostate carcinoma patients with low H3K4me2, independently of other clinical and pathologic parameters (Seligson et al., 2005). H3K4 methylation is established by the SET1 and mixed lineage leukemia (MLL) family of HMTs (Ruthenburg et al., 2007) and removed by the lysine-speci?c histone demethylase 1 (LSD1) and jumonji AT-rich interactive domain 1 (JARID1) family of HDMs (Klose and Zhang, 2007). These enzymes show altered activity in cancer. Chromosomal translocations of MLL lead to ectopic expression of various homeotic Hox genes and have a key role in leukemic progression (Krivtsov and Armstrong, 2007). SMYD3, another H3K4 HMT, is highly expressed in cancer and seems to correlate with the development and progression of colorectal, hepatocellular and breast carcinoma (Hamamoto et al., 2004, 2006). Expression levels of LSD1, a HDM which removes H3K4me/me2 marks, are signi?cantly elevated in bladder, lung, colorectal carcinoma and neuroblastoma (Schulte et al., 2009; Hayami et al., 2011). LSD1 expression correlates with adverse outcome and was inversely correlated with differentiation in neuroblastic tumors (Schulte et al., 2009). The JARID1 family of HDMs has the ability to reverse both the H3K4me2 and H3K4me3 modi?cation state. Fusion of RBBP2/JARID1A to nucleoporin-98 has been identi?ed in human leukemia, and was reported to generate potent oncoproteins that arrest hematopoietic differentiation and induce acute myeloid leukemia in rodent models (Wang et al., 2009). PLU-1/JARID1b, which is found upregulated in breast cancer, has an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1 (Lu et al., 1999; Yamane et al., 2007).

Trimethylation of H4K20 H4K20 methylation is associated with repressed chromatin (Nishioka et al., 2002; Schotta et al., 2004). In particular, H4K20me3 is found in constitutive heterochromatin regions (Kourmouli et al., 2004; Schotta et al., 2004; Gonzalo et al., 2005), and is enriched in regions of the chromatin which contain silenced genes (Henckel et al., 2009; Pauler et al., 2009). Overall, cancer cells exhibit a global decrease in the levels of H4K20me3 (Fraga et al., 2005; Tryndyak et al., 2006; Van Den Broeck et al., 2008). This reduction occurs in repetitive DNA sequences in association with the global loss of DNA methylation and loss of H4K16ac. Loss of H4K20me3 is as well observed in animal models of carcinogenesis (Kovalchuk et al., 2007; Bagnyukova et al., 2008). Moreover and in contrast, the presence of H4K20me3 has been correlated with the local silencing of genes during the development of cancers (Pogribny et al., 2007; Kwon et al., 2010). Methylation of H4K20 is complex and is catalyzed by several HMTs, including Pr-Set7 and Suv4-20 (Suv4-20h1 and Suv4-20h2). The bulk of the monomethylation on H4K20 is catalyzed primarily by Pr-Set7. H4K20me1 serves as a substrate for the Suv4-20 enzymes responsible for H4K20me2/3. A decrease in H4K20me3 levels in various cancer cell types is associated with diminished expression of Suv420h2 (Pogribny et al., 2006; Tryndyak et al., 2006; Van Den Broeck et al., 2008b).
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Acetylation/trimethylation of H3K9 Histone H3 lysine 9 trimethylation (H3K9me3) is a crucial epigenetic mark of heterochromatin and has been associated with transcriptional repression. On the other hand, the presence of acetylated H3K9 (H3K9ac) is considered to be a mark of active chromatin preventing the methylation of this residue and thereby found enriched at regions surrounding transcriptional start sites. In prostate and ovarian tumors, decrease of H3K9ac has been linked with tumor progression. In

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fact, the H3K9ac expression level correlates with histological grading and the clinical stage (Bai et al., 2008; Mohamed et al., 2007; Zhen et al., 2010). In agreement, a decrease in H3K9ac is coupled with a poor prognosis for these patients (Seligson et al., 2005; Zhen et al., 2010). In contrast, in hepatocellular carcinoma an increase in H3K9ac levels was reported (Bai et al., 2008). The decrease of H3K9Ac is required for the increase of H3K9me3, and similar to the acetylation status of H3K9, its methylation status has also been linked to cancer. An increase in H3K9 methylation, leading to aberrant gene silencing, has been found in various forms of cancer (Nguyen et al., 2002; Park et al., 2008; Pogribny et al., 2007) and high level of H3K9me3 were associated with poor prognosis in patients with gastric adenocarcinoma (Park et al., 2008). However, deregulation of this double histone mark (H3K9Ac/H3K9me3) in cancer cells is not necessarily associated with bad prognosis. In fact, patients with non-small cell lung adenocarcinoma or astrocytoma, and exhibiting reduced H3K9ac expression level have a better prognosis (Barlesi et al., 2007; Liu et al., 2010a). H3K9me3 deregulation in patients with acute myeloid leukemia, which occurs preferentially as a decrease in H3K9me3 levels at core promoter regions, is also associated with better prognosis (Muller-Tidow et al., 2010). These rather contradicting data suggest that the same histone modi?cation can predict opposite prognosis in different cancer types. Overexpression of G9a, a H3K9 HMT, has been reported in prostate, lung, liver, colon and breast cancers, which is in line with the increased H3K9me3 and loss of its counterpart H3K9ac in many cancers (Huang et al., 2010; Kondo et al., 2007; Kondo et al., 2008). Increased levels of G9a in patients with lung and liver cancer are associated with poor prognosis (Kondo et al., 2007; Kondo et al., 2008; Chen et al., 2010). Surprisingly, expression of GASC1, a H3K9 HDM, is also found ampli?ed in cancers including breast cancer (Cloos et al., 2006; Liu et al., 2009). Thus, both H3K9 HMT and H3K9 HDM are reported to be overexpressed in breast cancer. However, it is worthwhile to notice that these enzymes have different substrate speci?cities; G9a is a H3K9 speci?c dimethyltransferase, whereas GASC1 is mostly active on H3K9me3 (Maze et al., 2010). Thus, it is possible that G9a is more likely to affect gene expression, whereas GASC1 overexpression, on the other hand, will have a role in genomic instability (Chen et al., 2010).

Trimethylation of H3K27 Trimethylation of lysine 27 on histone H3 (H3K27me3), which is set by the Polycomb system, has been implicated in the formation of repressive chromatin domains. H3K27me3 spreads over large regions harboring many target genes and negatively regulates transcription by promoting a compact chromatin structure (Francis et al., 2004; Ringrose et al., 2004). H3K27me3 is frequently associated with gene silencing, especially

the repression of unwanted differentiation programs during lineage speci?cation (Bernstein et al., 2006; Barski et al., 2007; Mikkelsen et al., 2007). In human cancer, H3K27me3 has been evaluated as a prognostic factor in prostate, breast, ovarian, pancreatic and esophageal cancers (Yu et al., 2007; Wei et al., 2008; He et al., 2009; Tzao et al., 2009), however, some of the results are puzzling. The expression levels of H3K27me3 are signi?cantly higher in esophageal cancers and correlate with poor prognosis for patients (He et al., 2009; Tzao et al., 2009). H3K27me3 expression has also a prognostic value for clinical outcome in patients with breast, prostate, ovarian and pancreatic cancers (Wei et al., 2008). However, in these cancer types, patients with low expression of H3K27me3 had signi?cantly shorter overall survival time when compared with those with high H3K27me3 expression. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2, which mediates H3K27me3 (Hansen et al., 2008). Recent studies have showed that overexpression of EZH2 occurred in diverse cancers, including prostate, breast, renal and ovarian cancers, as well as glioblastoma multiforme (Varambally et al., 2002; Kleer et al., 2003; Orzan et al., 2010; Wagener et al., 2010). Overexpression of EZH2 has been associated with the invasion and progression of cancers, especially with the progression of prostate cancer (Yu et al., 2007). Generally, EZH2 overexpression in cancer cells seems to result in an EZH2-dependent increase in H3K27me3. However, Wei et al. (2008) found no association between EZH2 and H3K27me3 expression in breast, ovarian and pancreatic cancers. One explanation for the absence of correlation between EZH2 and H3K27me3 in these cancer types might lie in the H3K27me3 HDMs. H3K27me3 marks are removed by the HDMs JMJD3/KDM6B and UTX (Xiang et al., 2007). Inactivating somatic mutations of UTX were recently reported in a variety of tumors, particularly in multiple myeloma (van Haaften et al., 2009). JMJD3 has also been linked to tumor development. JMJD3 is induced by Epstein–Barr virus and overexpressed in Hodgkin’s lymphoma (Anderton et al., 2011). JMJD3 is also found upregulated in prostate cancer, and its expression is higher in metastatic prostate cancer (Xiang et al., 2007). In addition, inhibition of JMJD3 expression in mouse embryonic ?broblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization (Agger et al., 2009). Thus, there is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, demonstrating that a precise balance of this methylation is critical for normal cell growth (Martinez-Garcia and Licht, 2010).

Acetylation of H3K56 The unique feature of Histone H3 lysine 56 (H3K56) is its location in the nucleosome. H3K56 localizes at both
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the entry and exit points of a nucleosome, and it has been shown that histone–DNA interactions at the entry and exit points in the nucleosome are weakened by its acetylation (Masumoto et al., 2005). Although some studies have indicated that H3K56 acetylation (H3K56ac) is involved in transcription, several groups have shown that it is also involved in chromatin assembly during DNA replication and repair and contributes to genomic stability (Xu et al., 2005; Ru?ange et al., 2007; Das et al., 2009; Tjeertes et al., 2009; Yuan et al., 2009). The enzymatic machinery involved in its regulation is still controversial. In humans, both CBP/p300 and hGCN5 have been reported to acetylate H3K56 (Das et al., 2009; Tjeertes et al., 2009; Vempati et al., 2010). The mechanism regulating deacetylation of H3K56 is not less controversial; indeed not less than ?ve HDACs: SIRT1, SIRT2, SIRT3, HDAC1 and HDAC2 have been reported to deacetylate H3K56ac in humans (Das et al., 2009; Miller et al., 2010; Vempati et al., 2010; Yuan et al., 2009). Interestingly, analysis of occurrence of H3K56 acetylation using chromatin immunoprecipitation-on-chip revealed its genome-wide spread, affecting genes involved in several pathways that are implicated in tumorigenesis such as cell cycle, DNA damage response, DNA repair and apoptosis (Vempati et al., 2010). Furthermore, increased H3K56ac, as well as upregulated expression of its positive regulator ASF1A, has been observed in many cancers (Das et al., 2009; Tjeertes et al., 2009).

Acetylation of H4K12 Studies have shown that hypoacetylation of histone H4 lysine 12 (H4K12Ac) can be used as predictive biomarkers for cancer recurrence in the prostate (Seligson et al., 2005) and in non-small-cell lung cancer (Barlesi et al., 2007; Van Den Broeck et al., 2008). Global hypoacetylation of H4K12 was even considered to be informative of tumor stage for colorectal cancer (Ashktorab et al., 2009) and H4K12 hypoacetylation can be used as a predictive biomarker for cancer recurrence in the prostate (Seligson et al., 2005).

Histone variants It is not only histone marks but also the incorporation of speci?c histone variants that becomes altered in cancer cells. On angiogenic signaling, histone cell cycle regulation-defective homolog A (HIRA), a histone chaperone, induces the incorporation of lysine 56 acetylated histone H3.3 at the chromatin domain of VEGFR1 (Dutta et al., 2010). On HIRA depletion, the induction of VEGFR1 and other angiogenic genes is impaired. A direct link between histone variant expression and cancer development has recently been drawn by Khare et al. (2011). They showed that during sequential development of hepatocellular carcinoma, H2A and H2A.1 are overexpressed, whereas H2A.2 is decreased. The increased expression of H2A.1 has been linked to hyperproliferation (Khare et al., 2011). In addition, the histone variant macroH2A appears to suppress tumor progression of malignant melanoma through regulation of CDK8 (Kapoor et al., 2010). In fact, knockdown of macroH2A in low malignant melanoma cells increases proliferation and migration in vitro and growth and metastasis in vivo.

Acetylation of H3K18 The H3K18 acetylation (H3K18ac) mark is regarded as a general marker for active transcription. Loss of H3K18ac is correlated with poor prognosis in patients with prostate, pancreatic, lung, breast and kidney cancers (Seligson et al., 2005; Seligson et al., 2009; Elsheikh et al., 2009; Manuyakorn et al., 2010), and tumor grade suggesting loss of this modi?cation is an important event in tumor progression (Elsheikh et al., 2009). Consistent with this observation, the Kurdistani laboratory demonstrated that oncogenic transformation by the adenovirus protein e1a is accompanied by dramatic changes in the genomic location of H3K18 acetylation (Ferrari et al., 2008; Horwitz et al., 2008). In addition, H3K18 hypoacetylation even strongly correlated with an increased risk of tumor recurrence in patients with low-grade prostate cancer (Seligson et al., 2005). However, in contrast to the report that found that lower levels of H3K18ac predicts poor survival, low expression of this histone mark has been associated with a better prognosis for patients with esophageal squamous cell carcinoma or glioblastoma (Liu et al., 2010a; Tzao et al., 2009). This indicates, once again, that one histone modi?cation can predict opposite prognosis in different cancer types and that histone marks may possess tissue-speci?c features.
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Consequences of the histone onco-modi?cations Appropriate patterns of DNA methylation and histone modi?cations are required to maintain cell identity and its disturbance can contribute to cancer formation (Fuks, 2005; Figure 3).

Changes in gene expression The regulation of gene expression is generally associated with speci?c modi?cations of histone tails (Turner, 2000; Strahl and Allis, 2000; Jenuwein and Allis, 2001; Turner, 2007). H3K4me3 as well as H3K9ac are generally found in the promoter regions of actively transcribed genes, whereas repressive histone marks, such as H3K27me3, H3K9me3 and H4K20me3, are responsible for transcriptional repression at promoter regions (Fischle et al., 2003; Schotta et al., 2004). It is striking to note that these histone modi?cations, which are believed to be important for gene expression control, have all been

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DNA repair alterations genomic instability aberrant gene expression cell cycle checkpoint alterations

demethylated H3K4 as well as CpG island DNA methylation, all of which are lost in cancer cells (Fournier et al., 2002; Ooi et al., 2007; Henckel et al., 2009).

Cell cycle checkpoint instability
H3K4 H3K9 H3K9 H3K27 H3K56 H4K16 H4K20
Me Me Ac Me Ac Ac Me

Figure 3 Functional consequences of histone onco-modi?cations. Speci?c histone modi?cations, which have been shown to occur in cancer cells, are displayed and their implication in cancer associated processes, such as aberrant gene expression (in green), genomic instability (in purple), DNA repair (in orange) and cell cycle checkpoint alterations (in blue). ac, acetylated; H, histone; K, lysine; me, methylated.

It is crucial that DNA replication takes place only once during the cell cycle, as its deregulation can result in multiple copies of chromosomes in daughter cells. This process is kept under strict control by the cell cycle checkpoints. In this respect it is quite interesting that cdk inhibitors, which are vital cell cycle checkpoint control components, are epigenetically silenced in cancer. In addition, the H3K4 HMT MLL1 has been described to regulate cell cycle checkpoint integrity and its fusion proteins described in several cancers compromise the S-phase checkpoints (Liu et al., 2010b). In addition, PR-Set7 an H4K20me HMT has also been shown to regulate the S-phase checkpoints (Jorgensen et al., 2007). In fact, Pr-Set7-dependent H4K20 methylation during S-phase is an essential posttranslational mechanism that ensures genome replication and stability (Tardat et al., 2007).

Impaired DNA repair found deregulated in cancer cells. In fact, alterations in modi?cations of histones have been linked to deregulated expression of many genes with important roles in cancer (summarized in Table 1). Silencing at heterochromatin causing genomic instability Widespread changes in the histone landscape, which occur independently of apparent sequence-speci?c DNA-binding proteins, are referred to as global histone modi?cations. Similar to their targeted effects, the global activity of the histone-modifying enzymes can modulate gene activity, but in addition, global modi?cations affect constitutively silenced regions of DNA (Vogelauer et al., 2000). A global loss in DNA methylation and repressive histone modi?cations at heterochromatin regions leads to genomic instability. Transposons are mobile DNA segments that can disrupt gene function by inserting in or near genes. Therefore, they are potentially mutagenous pieces of DNA but their mobility is normally kept under tight control using both DNA methylation and H3K9me2/me3 (Ebbs et al., 2005). Loss of these repressive epigenetic markers increases the random translocation of transposon elements, and hastens the onset of cancer. Similarly, through imprinting, entire chromosomes or chromosome sections are kept silenced to ensure appropriate levels of gene transcription. Loss of imprinting is a feature of genomic instability in cancer, which often leads to the silencing of tumor suppressors and overexpression of oncogenes. Imprinted regions are associated with H3K9me3, H4K20me3 and H3K27me3, The faithful replication of DNA and the ability to repair DNA accurately is important for the maintenance of genomic integrity. Exposure to genotoxic agents, results in DNA damage-induced double strand breaks, an overreliance on DNA repair mechanisms, a build-up of mutations and eventually cancer. Histone acetylation also occurs during the DNA damage response, although its role is less well studied than histone phosphorylations or ubiquitylations. H4K16ac has been shown to be required, along with gammaH2AX, for the recruitment of Mdc1, a DNA repair complex adapter protein, to sites of DNA damage (Li et al., 2010). In addition, H3K56ac and H3K9ac have been shown to be downregulated by DNA damage (Tjeertes et al., 2009). However, others have reported rather an accumulation of H3K56ac on DNA damage (Das et al., 2009; Yuan et al., 2009). H4K20me1/2 is recognized by the checkpoint mediator 53BP1, which targets it to sites of DNA damage (Jorgensen et al., 2007). Loss of these histone modi?cations could explain the impaired DNA damage response in cancer cells. However, the involvement of acetylated and methylated histone marks in the DNA damage response is not well de?ned yet and needs further research.

Perspectives We propose the use of a new terminology ‘histone oncomodi?cations’ to describe the covalent post-translational modi?cations of histones which have been linked to cancer. This epigenetic term is built as its genetic
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Table 1 Genes deregulated by post-translational histone modi?cations in cancer

, ,

counterpart ‘onco-gene’. This new term will take into account the active contribution and importance of these histone modi?cations in the development of cancer. Until now, cancer cell epigenetics has essentially been focused on DNA methylation. However, cancer cell speci?c patterns of histone modi?cations can offer an explanation for how cancer cells acquire a DNA methylation pattern distinct from their normal counterpart. Indeed, models have been proposed in which histone modi?cations guide DNA methylating enzymes (Fuks, 2005; Cedar and Bergman, 2009). Consequently, deregulation of histone modifying enzymes can result in the epigenetic silencing of tumor-suppressor genes by the recruitment of DNA methyltransferases. One remarkable example has been exposed in Glioma cells, where the DNA methytransferase 1 (DNMT1) is signi?cantly found overexpressed. Nevertheless, the DNA methyltransferase 1 promoter exhibits no changes in DNA methylation level in the cancer cells. In contrast, a differential histone code with distinct active marks, AcH3, AcH4, and H3k4me2, was detected in tumors, unlike in normal brain tissues, which were found predominantly enriched with repressive marks such as H3K9me2 and H3K27me3 (Rajendran et al., 2011). The exact sequence of events and the interactions between the enzymes controlling DNA methylation and histone modi?cations in cancer remains to be discovered.
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Considering the interdependence between the different histone marks, but also their interactions with DNA methylation and non-coding RNAs, the involvement of a large number of histone modi?cations in cancer development is not surprising. For instance, several histone-modifying enzymes, such as HDAC1, which is often found deregulated in cancer, can target and thereby modify several histone residues. Direct physical interactions between histone modifying enzymes have also been established. One example is the complex including MLL1 and hMOF, which combines H3K4 HMT and H4K16 histone acetyltransferase activities and can thereby regulate two histone oncomodi?cations described in this review (Dou et al., 2005). The consequences of histone onco-modi?cations on carcinogenesis are diverse and involve local as well as global effects. Among the global effects, the loss of genomic stability through loss of transposon silencing, cell cycle checkpoint instability and loss of imprinting are major events. DNA repair can also be impaired by an alteration in the histone landscape. Interestingly histone onco-modi?cations have been linked to all hallmarks of cancer described by Hanahan and Weinberg (2000). Thus, a growing number of pro-apoptotic genes have been described to be downregulated by epigenetic gene silencing. In addition, an upregulation in anti-apoptotic proteins has also been described (Hajji

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et al., 2008). Sustained angiogenesis, metastasis and invasion, insensitivity to growth inhibitors, self-suf?ciency in growth signals and limitless replicative potential have been all linked to histone modi?cations described in this review. Considering the contribution of histone onco-modi?cations to the hallmarks of cancer, these histone marks might represent useful prognostic biomarker. In practice, it was established that a lower degree of global levels of histone modi?cations serves as a prognostic marker for poor clinical outcome and an increased risk of tumor recurrence (Kurdistani, 2011). Thus, histone modi?cation patterns, like DNA methylation patterns, can be used as prognostic tool. In addition, because of the reversibility of histone modi?cations, approaches that target histone onco-modi?cation in the treatment of cancer could be the next wave in cancer therapeutics. Several drugs, which target histone-modifying enzymes, are already in the clinic or are undergoing clinical trials (http://www.clinicaltrials.org). As an illustration, suberoylanilide hydroxamic acid (vorinostat), a highly speci?c and potent HDAC inhibitor is approved by FDA for therapy of cutaneous T-cell lymphoma (Mann et al., 2007). However, as HDACs have a huge number of non-histone targets, non-epigenetic effects for the HDAC inhibitors cannot be excluded in their clinical success. The histone onco-modi?cations we described in this review and their roles in carcinogenesis are only the tip of the iceberg. An increasing number of cancer types are tested on a far larger set of possible histone modi?cations and new patterns in the histone landscape are likely to be uncovered in the future. Gaining deeper insights into the causes as well as the consequences of aberrant histone modi?cations will extend our understanding of cancer biology. One of many histone oncomodi?cation candidates could be the acetylation of H2B-K15, which has been found to be a property of non-dying cells. The loss of this histone mark is required for the appearance of the H2B-S14ph apoptotic mark (Ajiro et al., 2010). Therefore, these histone modi?cations might provide an additional link between apoptosis resistance and histone modi?cations. Increasing our knowledge about the complex interplay between the different histone onco-modi?cations, but also their

interactions with DNA methylation and non-coding RNA will create a complex picture of cancer epigenetics, which might explain many environmental effects of carcinogenesis and help in the prognosis and therapy of malignancies. Abbreviations
53BP1, tumor protein p53 binding protein 1; ac, acetylated; ASF1A, anti-silencing function 1 homolog A; BRCA1, breast cancer 1, early onset; CDK8, cyclin dependent kinase 8; ChIP, chromatin immunoprecipitation; CpG, cytosine-phosphateguanine; DBC1, deleted in breast cancer 1; DNMT, DNA methyltransferase; EZH2, Enhancer of zeste homolog 2; GASC1, gene ampli?ed in squamous cell carcinoma 1; H2A, histone 2A; H2B, histone 2B; H3, histone 3; H4, histone 4; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACI, HDAC inhibitor; HDM, histone demethylase; HIRA, histone cell cycle regulation-defective homolog A; hMOF, human orthologue of the Drosophila melanogaster males absent on the ?rst gene; HMT, histone methyltransferase; JARID1, jumonji AT-rich interactive domain 1; JMJD3, jumonji domain containing 3; K, lysine; me, methylated; LSD1, lysine-speci?c histone demethylase 1; Mdc1, mediator of DNA-damage checkpoint 1; mH2A, macro histone 2A; MLL, mixed lineage leukaemia; S, serine; SIRT1, sirtuin 1; SMYD3, SET and MYND domain-containing protein 3; T, threonine; ub, ubiquitinylated; UTX, ubiquitously transcribed tetratricopeptide repeat, X chromosome; Vegfr1, vascular endothelial growth factor receptor 1.

Con?ict of interest The authors declare no con?ict of interest.
Acknowledgements We apologize to authors whose primary references could not be cited owing to space limitations. JF is supported by a fellowship from Karolinska Institutet Foundations (KID medel). This work was supported by the Swedish Cancer Society, the Swedish Research Council, and the Karolinska Institutet Foundations (KI Cancer).

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