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Oncogene (2011) 30, 3391–3403 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW onco-modifications

JFu¨llgrabe, E Kavanagh and B Joseph

Department of Oncology-Pathology, Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden

Post-translational modification of provides an (Luger et al., 1997). In , an octamer of important regulatory platform for processes such as histones-2 copies of each of the four core histone expression, DNA replication and repair, 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 , the fundamental unit of . 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 , can contribute to the development of somes and the ‘string’ being the linker DNA. Linker a variety of human . As a conclusion, a new histones, such as , 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 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 of and of lysines and as well as and threonine Keywords: histone modification; histone-modifying , ubiquitylation, glycosylation, enzymes; carcinogenesis; acetylation; methylation sumoylation, adenosine diphosphate ribosylation and carbonylation, all of which are carried out by histone- modifying 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 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 recognition modules, cleosome positioning has revealed a plethora of events such as the or , 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 (HMTs), which pro- Correspondence: Dr B Joseph, Department of Oncology-Pathology, mote or inhibit depending on the target Karolinska Institutet, Cancer Centrum Karolinska, R8:03, Stockholm- histone residue; and histone (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 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 and (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 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 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 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 , 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, 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 , 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 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 the regulation of a regions of the genome early during tumorigenesis might variety of normal and disease-related processes. Thus predispose cells to genomic instability and further considering the fundamental roles of histone modifica- genetic changes (Robertson, 2005). Aberrant hyper- tions, it is not surprising that aberrations in in cancer usually occurs at CpG islands, modifications are discovered in cancer (Sharma et al., and the resulting changes in chromatin structure 2010) (Figure 1b). However, only a few of the more than effectively silence transcription. Cancer cells frequently 60 residues of histones in which modifications have been acquire aberrant methylation of multiple tumor-related described have been linked to cancer until now that cooperate to confer a survival advantage to (Kouzarides, 2007). In addition, several of the histone- the neoplastic cells (Baylin and Ohm, 2006). Compiling modifying enzymes have also been described to be evidence revealed that genes involved in cell-cycle altered in cancer cells (Figure 2). regulation, tumor cell invasion, DNA repair, , cell signaling, transcription and apoptosis are aberrantly hypermethylated and silenced in nearly Acetylation of H4K16 every tumor. DNA methyltransferases are responsible for establishing and maintenance of DNA methylation Global loss of acetylation of at lysine 16 patterns, which bring stable long-term gene repression. (), together with loss of trimethylation of However, it has recently become evident that DNA histone H4 at lysine 20 (H4K20me3) has been observed methylation and histone modification pathways can be along with DNA hypomethylation at repetitive DNA dependent on one another, and that this cross-talk can sequences in various primary tumors and were the first be mediated by biochemical interactions between HMTs histone marks reported deregulated in cancer cells and DNA methyltransferases (Tachibana et al., 2008; (Fraga et al., 2005). Unlike most histone modifications, Cedar and Bergman, 2009; Zhao et al., 2009). H4K16ac is unique for regulating higher-order chroma- CpG-island hypermethylation in cancer cells is asso- tin structures beyond the level of nucleosomes. Indeed, ciated to a particular pattern of histone marks including this single histone modification influences functional deacetylation of histones H3 and H4, loss of interactions between histones and the chromatin fiber, lysine trimethylation, and gain of H3K9 methylation providing a potential mechanism to regulate chromatin and H3K27 trimethylation. Although some studies folding (Shogren-Knaak et al., 2006; Shogren-Knaak suggest that DNA methylation patterns guide histone and Peterson, 2006). Loss of this mark leads to a more

LSD1 JARID1a UTX MLL JARID1b JMJD3 SIRT1 SMYD3 EZH2 hMOF GASC1 G9a Suv4-20h2

Me Me K Me Me 56 Ac

H3 NH2- K K K KK-NH2 H4 4 92027 Ac 16

up-regulation down-regulation ASF1A

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-modifications 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.

Oncogene Histone onco-modifications JFu¨llgrabe et al 3394 ‘relaxed’ chromatin conformation, which might con- Di- and trimethylation of H3K4 tribute to genome instability. By now, loss of H4K16ac has been reported for several cancer types and was Di- and trimethylation of histone H3 at lysine 4 shown to influence cancer cell sensitivity to chemother- (H3K4me2/me3) is associated with transcriptional apy (Elsheikh et al., 2009; Fraga et al., 2005; Hajji et al., competence and activation, with the highest levels 2010). Reduction in H4K16ac correlates with tumor observed near transcriptional start sites of highly progression (Fraga et al., 2005). hMOF (human expressed genes (Shi et al., 2004). A decrease of orthologue of the Drosophila melanogaster males absent H3K4me2/me3 is observed in a range of neoplastic on the first gene) is the major enzyme that acetylates tissues and may serve as a predictive factor for clinical H4K16 (Neal et al., 2000). Unlike most histone outcome for some of them (Seligson et al., 2005; Barlesi acetyltransferases that target multiple sites on histones, et al., 2007; Elsheikh et al., 2009; Ellinger et al., 2010; hMOF activity is restricted to residue 16 on the histone Manuyakorn et al., 2010; Rajendran et al., 2011). In H4 tail (Taipale et al., 2005; Utley and Cote, 2003). particular, tumor recurrence occurs earlier in low-grade Worth a notice, hMOF expression is frequently down- prostate patients with low H3K4me2, in- regulated in primary breast carcinoma and medullo- dependently of other clinical and pathologic parameters blastoma and constitutes for the latter a biomarker for (Seligson et al., 2005). H3K4 methylation is established clinical outcome (Pfister et al., 2008). hMOF loss of by the SET1 and mixed lineage leukemia (MLL) family function leads to defects in the and genome of HMTs (Ruthenburg et al., 2007) and removed by the instability (Taipale et al., 2005). H4K16ac is deacety- lysine-specific histone 1 (LSD1) and ju- lated by the NAD-dependent HDAC 1 (SIRT1). monji AT-rich interactive domain 1 (JARID1) family of Increased expression of SIRT1 has been reported in HDMs (Klose and Zhang, 2007). These enzymes show various tumors, and its use as a prognostic indicator has altered activity in cancer. Chromosomal translocations been proposed (Chen et al., 2005; Hida et al., 2007; of MLL lead to ectopic expression of various homeotic Huffman et al., 2007). In addition, a gene designated Hox genes and have a key role in leukemic progression ‘deleted in breast cancer 1’ (DBC1), which encodes a (Krivtsov and Armstrong, 2007). SMYD3, another negative regulator of sirtuin 1 (Cha et al., 2009; Jang H3K4 HMT, is highly expressed in cancer and seems et al., 2008), also holds significant prognostic value for to correlate with the development and progression breast, gastric and lung carcinoma (Cha et al., 2009; of colorectal, hepatocellular and breast carcinoma Lee et al., 2011). (Hamamoto et al., 2004, 2006). Expression levels of LSD1, a HDM which removes H3K4me/me2 marks, are significantly elevated in bladder, lung, colorectal carci- noma and neuroblastoma (Schulte et al., 2009; Hayami Trimethylation of H4K20 et al., 2011). LSD1 expression correlates with adverse outcome and was inversely correlated with differentia- H4K20 methylation is associated with repressed chro- tion in neuroblastic tumors (Schulte et al., 2009). matin (Nishioka et al., 2002; Schotta et al., 2004). In The JARID1 family of HDMs has the ability to reverse particular, H4K20me3 is found in constitutive hetero- both the H3K4me2 and modification state. chromatin regions (Kourmouli et al., 2004; Schotta Fusion of RBBP2/JARID1A to nucleoporin-98 has et al., 2004; Gonzalo et al., 2005), and is enriched in been identified in human leukemia, and was reported to regions of the chromatin which contain silenced genes generate potent oncoproteins that arrest hematopoietic (Henckel et al., 2009; Pauler et al., 2009). Overall, cancer differentiation and induce acute myeloid leukemia in cells exhibit a global decrease in the levels of H4K20me3 rodent models (Wang et al., 2009). PLU-1/JARID1b, (Fraga et al., 2005; Tryndyak et al., 2006; Van Den which is found upregulated in breast cancer, has Broeck et al., 2008). This reduction occurs in repetitive an important role in the proliferative capacity of DNA sequences in association with the global loss of breast cancer cells through repression of tumor sup- DNA methylation and loss of H4K16ac. Loss of pressor genes, including BRCA1 (Lu et al., 1999; H4K20me3 is as well observed in animal models of Yamane et al., 2007). 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 Acetylation/trimethylation of H3K9 et al., 2007; Kwon et al., 2010). Methylation of H4K20 is complex and is catalyzed by several HMTs, including Histone H3 lysine 9 trimethylation () is a Pr-Set7 and Suv4-20 (Suv4-20h1 and Suv4-20h2). The crucial epigenetic mark of and has bulk of the monomethylation on H4K20 is catalyzed been associated with transcriptional repression. On the primarily by Pr-Set7. H4K20me1 serves as a substrate other hand, the presence of acetylated H3K9 () for the Suv4-20 enzymes responsible for H4K20me2/3. is considered to be a mark of active chromatin A decrease in H4K20me3 levels in various cancer cell preventing the methylation of this residue and thereby types is associated with diminished expression of Suv4- found enriched at regions surrounding transcriptional 20h2 (Pogribny et al., 2006; Tryndyak et al., 2006; Van start sites. In prostate and ovarian tumors, decrease of Den Broeck et al., 2008b). H3K9ac has been linked with tumor progression. In

Oncogene Histone onco-modifications JFu¨llgrabe et al 3395 fact, the H3K9ac expression level correlates with the repression of unwanted differentiation programs histological grading and the clinical stage (Bai et al., during lineage specification (Bernstein et al., 2006; 2008; Mohamed et al., 2007; Zhen et al., 2010). In Barski et al., 2007; Mikkelsen et al., 2007). In human agreement, a decrease in H3K9ac is coupled with a poor cancer, has been evaluated as a prognostic prognosis for these patients (Seligson et al., 2005; Zhen factor in prostate, breast, ovarian, pancreatic and et al., 2010). In contrast, in hepatocellular carcinoma an esophageal cancers (Yu et al., 2007; Wei et al., 2008; increase in H3K9ac levels was reported (Bai et al., 2008). He et al., 2009; Tzao et al., 2009), however, some of the The decrease of H3K9Ac is required for the increase of results are puzzling. The expression levels of H3K27me3 H3K9me3, and similar to the acetylation status of are significantly higher in esophageal cancers and H3K9, its methylation status has also been linked to correlate with poor prognosis for patients (He et al., cancer. An increase in H3K9 methylation, leading to 2009; Tzao et al., 2009). H3K27me3 expression has also aberrant gene silencing, has been found in various forms a prognostic value for clinical outcome in patients with of cancer (Nguyen et al., 2002; Park et al., 2008; breast, prostate, ovarian and pancreatic cancers Pogribny et al., 2007) and high level of H3K9me3 were (Wei et al., 2008). However, in these cancer types, associated with poor prognosis in patients with gastric patients with low expression of H3K27me3 had adenocarcinoma (Park et al., 2008). However, deregula- significantly shorter overall survival time when com- tion of this double histone mark (H3K9Ac/H3K9me3) pared with those with high H3K27me3 expression. in cancer cells is not necessarily associated with bad of zeste homolog 2 (EZH2) is the catalytic prognosis. In fact, patients with non-small cell lung subunit of the polycomb repressive complex 2, which adenocarcinoma or astrocytoma, and exhibiting reduced mediates H3K27me3 (Hansen et al., 2008). Recent H3K9ac expression level have a better prognosis (Barlesi studies have showed that overexpression of EZH2 et al., 2007; Liu et al., 2010a). H3K9me3 deregulation in occurred in diverse cancers, including prostate, breast, patients with acute myeloid leukemia, which occurs renal and ovarian cancers, as well as glioblastoma preferentially as a decrease in H3K9me3 levels at core multiforme (Varambally et al., 2002; Kleer et al., 2003; promoter regions, is also associated with better prog- Orzan et al., 2010; Wagener et al., 2010). Overexpression nosis (Muller-Tidow et al., 2010). These rather contra- of EZH2 has been associated with the invasion and dicting data suggest that the same histone modification progression of cancers, especially with the progression can predict opposite prognosis in different cancer types. of prostate cancer (Yu et al., 2007). Generally, EZH2 Overexpression of G9a, a H3K9 HMT, has been overexpression in cancer cells seems to result in an reported in prostate, lung, liver, colon and breast EZH2-dependent increase in H3K27me3. However, Wei cancers, which is in line with the increased H3K9me3 et al. (2008) found no association between EZH2 and and loss of its counterpart H3K9ac in many cancers H3K27me3 expression in breast, ovarian and pancreatic (Huang et al., 2010; Kondo et al., 2007; Kondo et al., cancers. One explanation for the absence of correlation 2008). Increased levels of G9a in patients with lung and between EZH2 and H3K27me3 in these cancer types liver cancer are associated with poor prognosis (Kondo might lie in the H3K27me3 HDMs. H3K27me3 et al., 2007; Kondo et al., 2008; Chen et al., 2010). marks are removed by the HDMs JMJD3/KDM6B Surprisingly, expression of GASC1, a H3K9 HDM, is and UTX (Xiang et al., 2007). Inactivating somatic also found amplified in cancers including breast cancer of UTX were recently reported in a variety (Cloos et al., 2006; Liu et al., 2009). Thus, both H3K9 of tumors, particularly in multiple myeloma (van HMT and H3K9 HDM are reported to be over- Haaften et al., 2009). JMJD3 has also been linked to expressed in breast cancer. However, it is worthwhile tumor development. JMJD3 is induced by Epstein–Barr to notice that these enzymes have different substrate virus and overexpressed in Hodgkin’s lymphoma specificities; G9a is a H3K9 specific dimethyltransferase, (Anderton et al., 2011). JMJD3 is also found upregu- whereas GASC1 is mostly active on H3K9me3 (Maze lated in prostate cancer, and its expression is higher in et al., 2010). Thus, it is possible that G9a is more likely metastatic prostate cancer (Xiang et al., 2007). In to affect , whereas GASC1 overexpres- addition, inhibition of JMJD3 expression in mouse sion, on the other hand, will have a role in genomic embryonic fibroblasts results in suppression of instability (Chen et al., 2010). p16Ink4a and p19Arf expression and in their immorta- lization (Agger et al., 2009). Thus, there is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, demonstrat- Trimethylation of H3K27 ing that a precise balance of this methylation is critical for normal cell growth (Martinez-Garcia and Licht, Trimethylation of lysine 27 on histone H3 (H3K27me3), 2010). which is set by the Polycomb system, has been implicated in the formation of repressive chromatin domains. H3K27me3 spreads over large regions harbor- ing many target genes and negatively regulates tran- Acetylation of H3K56 scription by promoting a compact chromatin structure (Francis et al., 2004; Ringrose et al., 2004). H3K27me3 The unique feature of Histone H3 lysine 56 (H3K56) is is frequently associated with gene silencing, especially its location in the nucleosome. H3K56 localizes at both

Oncogene Histone onco-modifications JFu¨llgrabe et al 3396 the entry and exit points of a nucleosome, and it has Acetylation of H4K12 been shown that histone–DNA interactions at the entry and exit points in the nucleosome are weakened by its Studies have shown that hypoacetylation of histone H4 acetylation (Masumoto et al., 2005). Although some lysine 12 () can be used as predictive studies have indicated that H3K56 acetylation biomarkers for cancer recurrence in the prostate () is involved in transcription, several groups (Seligson et al., 2005) and in non-small-cell have shown that it is also involved in chromatin (Barlesi et al., 2007; Van Den Broeck et al., 2008). assembly during DNA replication and repair and Global hypoacetylation of H4K12 was even considered contributes to genomic stability (Xu et al., 2005; to be informative of tumor stage for colorectal cancer Rufiange et al., 2007; Das et al., 2009; Tjeertes et al., (Ashktorab et al., 2009) and H4K12 hypoacetylation 2009; Yuan et al., 2009). The enzymatic machinery can be used as a predictive biomarker for cancer involved in its regulation is still controversial. In recurrence in the prostate (Seligson et al., 2005). 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 contro- versial; indeed not less than five HDACs: SIRT1, It is not only histone marks but also the incorporation SIRT2, SIRT3, HDAC1 and HDAC2 have been of specific histone variants that becomes altered in reported to deacetylate H3K56ac in humans (Das cancer cells. On angiogenic signaling, histone cell cycle et al., 2009; Miller et al., 2010; Vempati et al., 2010; regulation-defective homolog A (HIRA), a histone Yuan et al., 2009). Interestingly, analysis of occurrence , induces the incorporation of lysine 56 of H3K56 acetylation using chromatin immunoprecipi- acetylated histone H3.3 at the chromatin domain of tation-on-chip revealed its genome-wide spread, affect- VEGFR1 (Dutta et al., 2010). On HIRA depletion, the ing genes involved in several pathways that are induction of VEGFR1 and other angiogenic genes is implicated in tumorigenesis such as cell cycle, DNA impaired. A direct link between histone variant expres- damage response, DNA repair and apoptosis (Vempati sion and cancer development has recently been drawn et al., 2010). Furthermore, increased H3K56ac, as well by Khare et al. (2011). They showed that during as upregulated expression of its positive regulator sequential development of hepatocellular carcinoma, ASF1A, has been observed in many cancers (Das H2A and H2A.1 are overexpressed, whereas H2A.2 is et al., 2009; Tjeertes et al., 2009). 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 Acetylation of H3K18 through regulation of CDK8 (Kapoor et al., 2010). In fact, knockdown of macroH2A in low malignant The H3K18 acetylation (H3K18ac) mark is regarded as melanoma cells increases proliferation and migration a general marker for active transcription. Loss of in vitro and growth and metastasis in vivo. 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 Consequences of the histone onco-modifications tumor grade suggesting loss of this modification is an important event in tumor progression (Elsheikh Appropriate patterns of DNA methylation and histone et al., 2009). Consistent with this observation, the modifications are required to maintain cell identity and Kurdistani laboratory demonstrated that oncogenic its disturbance can contribute to cancer formation transformation by the adenovirus protein e1a is (Fuks, 2005; Figure 3). accompanied by dramatic changes in the genomic location of H3K18 acetylation (Ferrari et al., 2008; Horwitz et al., 2008). In addition, H3K18 hypoacetyla- Changes in gene expression tion even strongly correlated with an increased risk of tumor recurrence in patients with low-grade prostate The regulation of gene expression is generally associated cancer (Seligson et al., 2005). However, in contrast to with specific modifications of histone tails (Turner, 2000; the report that found that lower levels of H3K18ac Strahl and Allis, 2000; Jenuwein and Allis, 2001; Turner, predicts poor survival, low expression of this histone 2007). H3K4me3 as well as H3K9ac are generally found mark has been associated with a better prognosis in the promoter regions of actively transcribed genes, for patients with esophageal squamous cell carcinoma whereas repressive histone marks, such as H3K27me3, or glioblastoma (Liu et al., 2010a; Tzao et al., 2009). H3K9me3 and H4K20me3, are responsible for tran- This indicates, once again, that one histone modification scriptional repression at promoter regions (Fischle et al., can predict opposite prognosis in different cancer types 2003; Schotta et al., 2004). It is striking to note that and that histone marks may possess tissue-specific these histone modifications, which are believed to be features. important for gene expression control, have all been

Oncogene Histone onco-modifications JFu¨llgrabe et al 3397 demethylated H3K4 as well as CpG island DNA DNA repair alterations methylation, all of which are lost in cancer cells (Fournier genomic instability et al., 2002; Ooi et al., 2007; Henckel et al.,2009). cell cycle checkpoint aberrant gene expression alterations

Cell cycle checkpoint instability

It is crucial that DNA replication takes place only once H3K4 Me during the cell cycle, as its deregulation can result in multiple copies of chromosomes in daughter cells. This K Me H3 9 process is kept under strict control by the cell cycle H3K9 Ac checkpoints. In this respect it is quite interesting that cdk inhibitors, which are vital cell cycle checkpoint H3K27 Me control components, are epigenetically silenced in cancer. In addition, the H3K4 HMT MLL1 has been K Ac H3 56 described to regulate cell cycle checkpoint integrity and H4K16 Ac its fusion proteins described in several cancers compro- mise the S-phase checkpoints (Liu et al., 2010b). In H4K20 Me addition, PR-Set7 an HMT has also been shown to regulate the S-phase checkpoints (Jorgensen Figure 3 Functional consequences of histone onco-modifications. et al., 2007). In fact, Pr-Set7-dependent H4K20 methy- Specific histone modifications, which have been shown to occur in cancer cells, are displayed and their implication in cancer lation during S-phase is an essential posttranslational associated processes, such as aberrant gene expression (in green), mechanism that ensures genome replication and stability genomic instability (in purple), DNA repair (in orange) and cell (Tardat et al., 2007). cycle checkpoint alterations (in blue). ac, acetylated; H, histone; K, lysine; me, methylated. Impaired DNA repair found deregulated in cancer cells. In fact, alterations in modifications of histones have been linked to deregu- The faithful replication of DNA and the ability to repair lated expression of many genes with important roles in DNA accurately is important for the maintenance of cancer (summarized in Table 1). genomic integrity. Exposure to genotoxic agents, results in DNA damage-induced double strand breaks, an over- reliance on DNA repair mechanisms, a build-up of Silencing at heterochromatin causing genomic instability mutations and eventually cancer. Histone acetylation also occurs during the DNA damage response, although Widespread changes in the histone landscape, which its role is less well studied than histone occur independently of apparent sequence-specific or ubiquitylations. H4K16ac has been shown to be DNA-binding proteins, are referred to as global histone required, along with gammaH2AX, for the recruitment modifications. Similar to their targeted effects, the of Mdc1, a DNA repair complex adapter protein, to global activity of the histone-modifying enzymes can sites of DNA damage (Li et al., 2010). In addition, modulate gene activity, but in addition, global mod- H3K56ac and H3K9ac have been shown to be down- ifications affect constitutively silenced regions of DNA regulated by DNA damage (Tjeertes et al., 2009). (Vogelauer et al., 2000). A global loss in DNA However, others have reported rather an accumulation methylation and repressive histone modifications at of H3K56ac on DNA damage (Das et al., 2009; Yuan heterochromatin regions leads to genomic instability. et al., 2009). H4K20me1/2 is recognized by the Transposons are mobile DNA segments that can disrupt checkpoint mediator 53BP1, which targets it to sites of gene function by inserting in or near genes. Therefore, DNA damage (Jorgensen et al., 2007). Loss of these they are potentially mutagenous pieces of DNA but histone modifications could explain the impaired DNA their mobility is normally kept under tight control using damage response in cancer cells. However, the involve- both DNA methylation and /me3 (Ebbs et al., ment of acetylated and methylated histone marks in the 2005). Loss of these repressive epigenetic markers DNA damage response is not well defined yet and needs increases the random translocation of transposon further research. elements, and hastens the onset of cancer. Similarly, through imprinting, entire chromosomes or chromo- some sections are kept silenced to ensure appropriate Perspectives levels of gene transcription. Loss of imprinting is a feature of genomic instability in cancer, which often We propose the use of a new terminology ‘histone onco- leads to the silencing of tumor suppressors and modifications’ to describe the covalent post-transla- overexpression of oncogenes. Imprinted regions are tional modifications of histones which have been linked associated with H3K9me3, H4K20me3 and H3K27me3, to cancer. This epigenetic term is built as its genetic

Oncogene Histone onco-modifications JFu¨llgrabe et al 3398 Table 1 Genes deregulated by post-translational histone modifications in cancer

, ,

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

Oncogene Histone onco-modifications JFu¨llgrabe et al 3399 et al., 2008). Sustained angiogenesis, metastasis and interactions with DNA methylation and non-coding invasion, insensitivity to growth inhibitors, self-suffi- RNA will create a complex picture of , ciency in growth signals and limitless replicative which might explain many environmental effects of potential have been all linked to histone modifications carcinogenesis and help in the prognosis and therapy of described in this review. malignancies. Considering the contribution of histone onco-mod- ifications to the hallmarks of cancer, these histone marks might represent useful prognostic biomarker. In prac- Abbreviations tice, it was established that a lower degree of global levels of histone modifications serves as a prognostic 53BP1, tumor protein p53 binding protein 1; ac, acetylated; marker for poor clinical outcome and an increased risk ASF1A, anti-silencing function 1 homolog A; BRCA1, breast of tumor recurrence (Kurdistani, 2011). Thus, histone cancer 1, early onset; CDK8, cyclin dependent kinase 8; ChIP, modification patterns, like DNA methylation patterns, chromatin ; CpG, cytosine-- can be used as prognostic tool. In addition, because of guanine; DBC1, deleted in breast cancer 1; DNMT, DNA methyltransferase; EZH2, Enhancer of zeste homolog 2; the reversibility of histone modifications, approaches GASC1, gene amplified in squamous cell carcinoma 1; H2A, that target histone onco-modification in the treatment of histone 2A; H2B, histone 2B; H3, histone 3; H4, histone 4; cancer could be the next wave in cancer therapeutics. HAT, histone acetyltransferase; HDAC, ; Several drugs, which target histone-modifying enzymes, HDACI, HDAC inhibitor; HDM, histone demethylase; are already in the clinic or are undergoing clinical trials HIRA, histone cell cycle regulation-defective homolog A; (http://www.clinicaltrials.org). As an illustration, suberoy- hMOF, human orthologue of the Drosophila melanogaster lanilide hydroxamic acid (vorinostat), a highly specific and males absent on the first gene; HMT, histone methyltransfer- potent HDAC inhibitor is approved by FDA for therapy ase; JARID1, jumonji AT-rich interactive domain 1; JMJD3, of cutaneous T-cell lymphoma (Mann et al., 2007). jumonji domain containing 3; K, lysine; me, methylated; However, as HDACs have a huge number of non-histone LSD1, lysine-specific histone demethylase 1; Mdc1, mediator of DNA-damage checkpoint 1; mH2A, macro histone 2A; targets, non-epigenetic effects for the HDAC inhibitors MLL, mixed lineage leukaemia; S, serine; SIRT1, sirtuin 1; cannot be excluded in their clinical success. SMYD3, SET and MYND domain-containing protein 3; T, The histone onco-modifications we described in this threonine; ub, ubiquitinylated; UTX, ubiquitously transcribed review and their roles in carcinogenesis are only the tip tetratricopeptide repeat, ; Vegfr1, vascular of the iceberg. An increasing number of cancer types are endothelial growth factor receptor 1. tested on a far larger set of possible histone modifica- tions 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 Conflict of interest aberrant histone modifications will extend our under- standing of cancer biology. One of many histone onco- The authors declare no conflict of interest. modification 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 Acknowledgements for the appearance of the H2B-S14ph apoptotic mark We apologize to authors whose primary references could not (Ajiro et al., 2010). Therefore, these histone modifica- be cited owing to space limitations. JF is supported by a tions might provide an additional link between apopto- fellowship from Karolinska Institutet Foundations (KID sis resistance and histone modifications. Increasing our medel). This work was supported by the Swedish Cancer knowledge about the complex interplay between the Society, the Swedish Research Council, and the Karolinska different histone onco-modifications, but also their Institutet Foundations (KI Cancer).

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