Oncogene (2014) 33, 1207–1217 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc

REVIEW Context-specific regulation of cancer epigenomes by histone and factor

M Sarris, K Nikolaou and I Talianidis

Altered expression or activity of histone methylases and in cancer lead to aberrant modification patterns, which contribute to uncontrolled cell proliferation via cancer-specific deregulation of expression programs or the induction of genome instability. Several transcription factors that regulate growth-associated undergo lysine methylation, expanding the repertoire of regulatory targets modulated by histone-methylating during tumorigenesis. In certain specific tumor types or specific physiological conditions, these enzymes may trigger chromatin structure and/or activity changes that result in opposite effects on cancer initiation or progression. The mechanisms of such context-specific dual functions and those involved in the crosstalk between factor and histone modifications are subject to extensive research, which is beginning to shed light into this novel level of complexity of cancer-related epigenetic pathways.

Oncogene (2014) 33, 1207–1217; doi:10.1038/onc.2013.87; published online 18 March 2013 Keywords: cancer ; lysine methylation; histones; transcription factors

INTRODUCTION abnormal patterns of histone modification and DNA methylation. The basic unit of chromatin is the nucleosome, which consists of a Aberrant epigenetic mechanisms are manifested in both global histone octamer complex and a 146-bp DNA segment wrapped changes in chromatin packaging and in localized changes around it. This organizational framework of DNA has an important affecting transcription factor binding to specific promoters. The regulatory role in transcription by influencing the access and resulting cancer-specific epigenetic landscapes are in causative function of the transcriptional apparatus. Chromatin structure is relationship with the altered patterns, impaired highly dynamic and regulates not only transcription but also DNA repair, genomic instability or alterations in cell cycle checkpoints, which ultimately lead to oncogenic transformation virtually all DNA-templated processes including replication and 3,4 repair. Several types of factors that modulate chromatin structure and the development of cancer. are known. These include the ATP-dependent chromatin remodel- Tumor-specific alterations in the epigenetic chromatin modi- ing, which can alter nucleosome configuration or positioning fication patterns have been attributed to altered expression and coactivator/corepressor complexes, which possess enzymatic or activity (because of mutations) of several key chromatin- activities to covalently modify histones: histone acetyl- modifying enzymes. Over the past few years, several non-histone , deacetylases, methylases, demethylases and ubiqui- substrates for histone methylases and demethylases have been tin . The coordinated action of these complexes is a key described. Many of these targets are transcriptional regulators step in the creation of active or inactive states at the gene having crucial roles in proliferation control. Therefore, transcrip- regulatory regions.1 Analysis of the functional roles of these tion factor methylation may represent an additional important modifications has led to novel concepts proposing a ‘histone regulatory layer by which histone-modifying enzymes modulate code’ read by that modulate the transitions between cancer development. open and closed chromatin states.2 The combination of different An emerging area of interest is the dichotomous function of nucleosome modifications together with the dynamic deposition certain lysine methylases and demethylases in cancer, as cell type- of histone variants and the methylation of CpG islands, impart specific oncogenic or tumor-suppressive effects of some enzymes epigenetic marks on the genome, to establish and maintain is often observed in different human malignancies. In this review, specific patterns of gene expression, stability and we will summarize recent findings on the role of histone and ensure proper replication control.1 transcription factor methylation in cancer with focus on the In principle, if a certain combination of chromatin modifications variety of mechanisms that could explain their dual functions in over the genome is used to determine and maintain the different cancer types. differentiated state, then selective loss or overpresentation of modifications would result in a de-differentiated, developmentally plastic phenotype, such as those associated with tumors. Indeed, HISTONE LYSINE METHYLASES IN CANCER over the past decade it has become increasingly apparent that Lysine methylation occurs in several residues of the N-terminal virtually all human cancer types have epigenetic abnormalities tails or the globular domain of histones. Depending on the residue that collaborate with genetic changes to drive progressive stages and the degree of methylation (mono-, di- or trimethylation), of tumor progression.3 These abnormalities are presented as it has an important role in the generation of open or closed

Biomedical Sciences Research Center Alexander Fleming, Vari, Greece. Correspondence: Dr I Talianidis, Biomedical Sciences Research Center Alexander Fleming. 34, Alexander Fleming Street, Vari 16672, Athens, Greece. E-mail: talianidis@fleming.gr Received 19 December 2012; accepted 1 February 2013; published online 18 March 2013 Context-specific regulation of cancer epigenomes M Sarris et al 1208 chromatin configuration that regulates all DNA-templated biolo- is overexpressed in breast cancer, hepatocellular and colon gical processes.1 For example, histone 3 lysine 4 trimethylation carcinomas.48,49 The mechanism by which Smyd3 is involved in () correlates with open states of transcriptionally active cancer is obscure. It has been proposed that Smyd3 may induce chromatin. Other lysine associated with active states directly the expression of the WNT10B, N- and CRKL proto- are H3K36Me2/3, H3K79Me2/3 and H4K20Me1,1,5 while H3K9Me3, oncogenes or the telomerase gene TERT.49,78 Other reports H3K27Me3 and H4K20Me3 mark closed heterochromatin suggest that Smyd3 may promote proliferation via acting as domains.1,6 The methyl marks themselves are required for the coactivator of estrogen target genes.79 More recent generation of the above configurations, as they provide studies showed that the oncogenic function of Smyd3 is mediated a specialized surface recognized by ‘reader’ proteins.1 For by its direct stimulatory effect on matrix metalloproteinase example, H3K4Me3 marks bind the general transcription factor 9 expression, which has a central role in tumor progression, TAF3, which together with other components of the transcription metastasis and angiogenesis.80 Overexpression of Smyd2 (KMT3C), machinery activates transcription and maintains the open state of another member of the Smyd family, is frequently detected in the underlining chromatin.7 In contrast, HP1 or the LMBTL family primary esophageal squamous cell carcinomas.81 Its expression of proteins, which associate with H3K9Me3 or H4K20Me3, facilitate correlates with invasiveness, status of recurrence and the overall compaction of the local nucleosomes and reduce accessibility to rate of patient survival.81 Smyd2 was originally reported as an other proteins.6,8 H3K36 methylase.82 Subsequent studies revealed that similar to Except for the H3K79-specific methylase Dot1l (KMT4), all other Smyd3, it can also methylate H3K4 in the presence of HSP90.83 known histone lysine methylases (KMTs) share strong homology in Both modifications are linked to transcriptional activation, a 140 amino-acid catalytic domain known as the SET (Su(var)3-9, suggesting that Smyd2 oncogenic function may be mediated by Enhancer-of-zeste and Trithorax) domain.9 Interestingly, functional the activation of specific proliferation-associated genes. The target defects of most known histone lysine methylases have been genes of Smyd2 in cancer remain to be identified. observed in different cancer types (Table 1), pointing to a direct PR-SET7 (SETD8/ KMT5A) is the sole that generates relationship between cancer-specific alteration of histone methy- H4K20Me1, which can be further methylated by Suv4-20h1/2 to lation marks and the uncontrolled cell proliferation phenotype. A di-and trimethylated state.84 Both, PR-SET7 expression and wide range of aberrations affect the function of histone lysine H4K20Me1 are tightly regulated during the cell cycle, reaching methylases. They include overexpression, downregulation, mis- highest levels during G2/M and early G1 phase followed by sharp targeting, mutations and gene fusions caused by chromosomal decrease during S-phase.85 The main function of PR-SET7 is the translocations. maintenance of genome integrity, which is achieved via regulation The members of the MLL family catalyze H3K4 methylation and of diverse pathways. H4K20Me1 is required for recruiting 53BP1 partition in a large multiprotein complex containing several other to sites of DNA damage and initiate DNA repair process.86 chromatin remodeling factors.72 More than 70% of infant H4K20 methylation alters chromatin compaction and mitotic and approximately 10% of adult human leukemias condensation, thereby affecting higher order chromatin display chromosomal translocations of the MLL (KMT2A) gene with structure.87 PR-SET7 and H4K20 methylation is also required for 450 functionally diverse MLL fusions having been identified.11 proper DNA replication by regulating replication fork stability However, only a subset of those accounts for the most frequent and coordinating replication licensing to prevent aberrant MLL rearrangements (80% of all MLL-translocation-bearing re-replication.88,89 Apart from its role in genome integrity, leukemias being the MLL–AF4; MLL–AF9; MLL–ENL; PR-SET7 may also trigger tumorigenesis via its transcription MLL–AF10 and/or MLL–AF6). AF4, AF9, AF10 and ENL regulatory function. It has been shown that PR-SET7 interacts belong to the family of serine/proline-rich nuclear proteins having with TWIST, a master regulator of epithelial–mesenchymal role in transcription elongation. It is interesting that in all fusion transition (EMT). The two proteins are functionally interdependent proteins the C terminal SET domain is lost and consequently in promoting EMT and in enhancing the metastatic potential they lack H3K4 activity.9 Despite this, the of breast cancer cells.90 Although the exact mechanism is not N-terminal fusions upregulate the expression of several target understood, it appears that PR-SET7-mediated H4K20 mono- genes including members of the Hox cluster,11 probably via the methylation in the presence of TWIST, activates the transcription function of the fusion partners facilitating transcription elongation. of N-cadherin gene and represses that of E-cadherin gene.90 The H3K79 methylase DOT1L is a component of menin- Importantly, in human breast carcinoma PR-SET7 expression was containing MLL-AF9 and MLL-ENL complexes formed in specific positively correlated with N-cadherin and TWIST expression or leukemias.52,73 Mistargeting of DOT1L by MLL fusions leads to metastasis and negatively correlated with E-cadherin expression, changes of methylation patterns from H3K4 to H3K79 of specific which points to the role of PR-SET7 in promoting EMT and the MLL target genes, which are crucial for oncogenic transformation invasive potential of breast cancer.90 in some leukemias.74 The other histone implicated in genome The NSD family of HMTs consists of three members NSD1 stability are those catalyzing H3K9 methylation and consequent (KMT3B), NSD2 (MMSET) and NSD3, which methylate H3K36. formation of large heterochromatin domains. They are Suv39H1 Defects in NSD1 function resulting from downregulation of (KMT1A), G9a (KMT1C), GLP1 (KMT1D), Setdb1 (KMT1E) and the its expression or fusion with the nucleoporin NUP98 or specific PRDM family of enzymes, whose malfunctioning is observed in mutations were observed in neuroblastomas, in myeloid various cancers (Table 1). H3K9 methylation, apart from its leukemias and in Sotos syndrome patients, respectively.32,75,76 involvement in gene silencing, has also been implicated in NSD2-MMSET is overexpressed in multiple myelomas.77 maintaining inactive genomic regions associated with the nuclear High levels of MMSET correlate with an increased H3K36 lamina,91 thus serving as a key determinant in the three- methylation and decreased H3K27 methylation across the dimensional nuclear architecture and chromatin arrangement genome, leading to the generation of large open chromatin within the nucleus. The potential role of nuclear architecture in domains. Loss of MMSET expression alters cell adhesion gene regulation is being increasingly appreciated, but is properties, suppresses growth and induces apoptosis by still poorly understood. Given the dramatic changes in affecting the expression of genes involved in cell cycle chromatin configurations and the large chromosomal deletions, regulation, and integrin signaling.77 translocations or amplifications observed in cancer, we envisage The Smyd family of enzymes contains a SET domain that is split that nuclear topology-related regulation of DNA-templated into two parts by a MYND domain/Zn-finger motif, implicated in processes could have an important role in inducing uncontrolled –protein interactions. The H3K4 methylase Smyd3 (KMT3E), proliferation during tumorigenesis.

Oncogene (2014) 1207 – 1217 & 2014 Macmillan Publishers Limited Context-specific regulation of cancer epigenomes M Sarris et al 1209 Table 1. Histone methyltransferases

Gene Histone target Cancer type Abberation Ref

MLL (KMT2A) /2/3 (AML, ALL) More than 50 MLL-fusions (:AF10, AF4, ELL, 10,11 ENL among those) AML MLL-PTD (partial tandem duplications) 12–14 MLL2 (KMT2D) H3K4me1/2/3 Medulloblastoma Inactivating mutations 15 NHL Inactivating mutations 16 MLL3 (KMT2C) H3K4me1/2/3 Medulloblastoma Inactivating mutations 15 EZH2 (KMT6) H3K27me2/3 B-cell lymphomas Mutation A677 17 Diffuse large B-cell lymphoma Mutation Y641 18 Myelo-neoplasms and myelofibrosis Mutations 19 Aggressive breast cancer Overexpression 20,21 Bladder tumor Overexpression 22 Prostate cancer Overexpression; loss of miR101; gene 23–25 amplification Melanoma Overexpression 26 Lymphomas Overexpression: loss of miR26a 27,28 Gastric cancer Overexpression 29 HCC Overexpression 30 NSD1 (KMT3B) H3K36me1/2/3 AML Nup98-NSD1 fusion and/or amplification 31,32 Sotos syndrome Mutations 33 Neuroblastoma and Gliomas cell lines Downregulation: promoter CpG methylation 34 NSD2/ MMSET H3K36me1/2/3 Colon, lung, bladder, skin, ovary, prostate, Overexpression 35,36 multiple myeloma Multiple myeloma Translocation IgH-MMSET fusion 37,38 NSD3 H3K36me1/2 AML t8;11(p11.2;p15) Nup98–NSD3 fusion 39 Breast cancer Loci amplification 40 SETD2 (KMT3A) H3K36me1/2/3 Renal cell carcinoma (ccRCC) Inactivating mutations 41,42 Suv39H2 (KMT1B) /3 B-cell lymphomas Knockout mice develop tumors 43 GLP1 (KMT1D) H3K9me1/2 Medulloblastoma Deletion; downregulation 44 G9a (KMT1C) H3K9me1/2 HCC Overexpression 30 SETDB1 (KMT1E) H3K9me2/3 Melanoma Amplification; overexpression 45 Smyd2 (KMT3C) H3K36me2 HCC, primary esophageal squamous cell Overexpression 46,47 H3K4me carcinomas Smyd3 (KMT3E) H3K4me2/3 HCC, colon cancer Overexpression 48 H4K20me3 Breast cancer Overexpression 49 Smyd4 Medulloblastoma Downregulation 44 Breast cancer Downregulation 50 PR-SET7 (KMT5A) H4K20me1 Non-small cell lung carcinoma, small cell Overexpression 51 lung carcinoma DOT1L (KMT4) H3K79me1/2/3 Leukemia (AML,ALL) MLL–AF10 fusions: aberrant DOTL1 activity 52 Leukemia (AML,ALL) MLL–AF4 fusions: aberrant DOTL1 activity 53 T-ALL, AML CALM–AF10 fusion: aberrant DOTL1 activity 54 PRDM1 Lymphoma Inactivating mutations and miR silencing 55–58 PRDM2 (KMT8) H3K9me1/2/3 Breast cancer Downregulation; promoter methylation 59,60 Colorectal cancer Frameshift mutations in PRDM2 gene 61 Diffuse B-cell lymphoma KO mice; missense mutations 62 Gastric cancer Frameshift mutations; promoter methylation 63,64 HCC Downregulation; promoter methylation 60,65,66 Lung cancer Downregulation 59,62 Neuroblastoma Downregulation 59 PRDM5 Breast cancer Downregulation; promoter methylation 67 Colorectal and gastric cancer Downregulation; promoter methylation 68 HCC Downregulation; promoter methylation 67 PRDM12 Chronic myeloid leukemia 9q microdeletions encompassing RRP14 and 69,70 PRDM12 PRDM14 Breast cancer Overexpression 71 Abbreviations: AML, ; ALL, acute lymphoid leukemia; HCC, Hepatocellular carcinoma; HMT, histone methyltransferase; NHL, non-Hodgkin lymphoma.

DUAL FUNCTIONS OF EZH2 AND CROSSTALKS BETWEEN cancer, prostate cancer and gastroinetstinal tumors (Table 1). Most HISTONE METHYLASES IN CANCER of the cancer-associated effects of EZH2 induction can be One of the best-studied histone methyltransferase in cancer is the explained by its transcriptional repression function. One of the enhancer of Zeste 2 homolog EZH2 (KMT6), the core enzymatic main target of PRC2 complex is the INK4A-ARF tumor-suppressor subunit of the polycomb repressive complex PRC2. EZH2 and locus.93,94 Other tumor-suppressor targets of EZH2 include ADRB2 PRC2 is the major repressor of differentiation-specific genes in and PSP94 in prostate cancer cells95,96 and BMPR1B in embryonic stem cells, thus contributing to the maintenance of glioblastoma.97 Apart from repressing tumor-suppressor genes, pluripotent state.92 EZH2 overexpression or activation by mutation overexpression of EZH2 induces genomic instability also through is detected in a variety of tumors, including lymphomas, breast transcriptional repression of DNA repair factors.98 In addition,

& 2014 Macmillan Publishers Limited Oncogene (2014) 1207 – 1217 Context-specific regulation of cancer epigenomes M Sarris et al 1210 PRC2 complex is also targeted to the E-cadherin promoter by a modification associated with active chromatin. The mechanism Snail, leading to its downregulation and consequent induction of involves EZH2-mediated repression of miR-203, miR-26a and miR-31 EMT.29,99 In most cases, EZH2 overexpression correlates with transcription, which are known tumor-suppressor micro RNAs. These tumor invasiveness and poor prognosis. miRNAs also regulate MMSET RNA levels. In this way, EZH2 Elevated expression of EZH2 in cancer cells can be generated by overexpression leads to derepression of MMSET mRNA and to multiple mechanisms. These include defects of /RB pathway, the elevated levels of MMSET protein. The interconnected repressive and upstream regulators of EZH2 expression and cancer-specific loss of activating histone methylation marks generated by the interplay of miR-101, which post-translationally control EZH2 levels.24,100 As both EZH2–microRNA–MMSET regulatory axis represents a novel regulatory E2F/RB pathway and miR-101 are deregulated in cancer, the strategy for the epigenetic control of cancer-related genes (Figure 1). question arises whether EZH2 overexpression should be viewed as A direct positive cooperation between methylases is operating a bystander phenomenon rather than the primary cause of in AF9-induced myeloid leukemia where a self renewal-associated malignancy. Moreover, potential controversy was generated by the transcriptional program regulates the maintenance of leukemo- discovery of inactivating mutations of the EZH2 gene in myeloid genic, poorly differentiated phenotype. In these cells, malignancies, pointing to a potential tumor-suppressor role of Myb-mediated upregulation of Smyd2, as part of the ‘leukemia EZH2.19 The context-specific dual function of EZH2 in oncogenesis stem cell’ signature, is required to preserve the MLL-AF9-induced could raise concerns about the use of EZH2 inhibitors in undifferentiated state.104 Although the mechanism underlining chemotherapy. It should be emphasized, however, that there are this leukemia maintenance is not known the above findings point majorgapsinourknowledgeconcerningthefunctioningofEZH2 to the potential operation of a hierarchical transcriptional cascade mutations. For example, inactivating somatic mutations and and positive cooperation between the methylases. deletions are heterozygous, and may not necessarily have a dominant effect. It is also unclear whether the mutations affect global changes and interfere with other chromatin functions like CONTEXT-SPECIFIC OPPOSING EFFECTS OF HISTONE DNA replication or repair. Importantly, recent studies revealed a DEMETHYLASES IN CANCER histone methyltransferase-independent function of EZH2 affecting Histone lysine methylation is dynamically regulated by histone nuclearfactor(NF)kB target gene activation in - demethyases possessing activities toward specific lysine residues. negative basal-like breast cancer cells.101 This illustrates the complexity and the variety of mechanisms EZH2 utilizes to stimulate oncogenesis and highlights the necessity of further studies focusing on the mechanistic aspects of EZH2 mutations in conjunction with the global and gene-specific H3K27 methylation status in the different malignancies. An important question that needs to be addressed by such mechanistic studies is the mode of action of overexpressed enzymes that are not incorporated into large protein complexes. For example, it is known that free EZH2 cannot methylate H3K27 in vitro. It is unlikely that all other components of the PRC2 complex are concurrently overexpressed in cancer cells. This suggests that either the enzymatic activity of EZH2 is not fundamental in all cases or other, so far unknown, factors may be required to cooperate with the ‘extra’ EZH2 molecules, which due to the substoichiometrical amounts of other components is not partitioning in PRC2 complex. Moreover, one can also envisage that the altered stoichiometry of complex components may also lead to the mistargeting of methylases. In line with the above scenarios is the finding that EZH2 proteins not assembled into PRC2 complex interact with the (AR) in castration-resistant prostate cancer cells and coactivate AR target genes.102 The findings of this report demonstrate that the switch of EZH2 function from polycomb repressor to transcriptional coactivator depends on phosphorylation of Ser21 by PI3K-Akt.102 As Ser21-phosphorylated EZH2 has lost H3K27 trimethylation activity, we speculate that inactivating EZH2 mutants observed in myeloid malignancies may utilize similar mechanisms. Future Figure 1. Schematic presentation of different layers of regulation by studies aimed at identifying EZH2-interacting proteins in different histone lysine methylases (HMT) and demethylases (HDM). Histone methylases generate specific modifications correlating gene silen- cancer types may shed light into this possibility. cing (for example, H3K9me; H3K27me) or gene activation As illustrated in the list of Table 1, deregulation of histone lysine (for example, H3K4me; H3K36me), which contribute to transcrip- methylases catalyzing modifications associated with either chro- tional activation or repression of oncogenes or tumor suppressors. matin compaction or transcriptional activation is equally observed These marks can be removed by HDMs. The same HDM may remove in different cancer types. A plausible mechanistic explanation for different modifications depending on the nature of the protein this is that enzymes generating marks associated with gene complex they partition or the interaction partner they recruit them activation (for example, MLLs, NSD2, Smyd2 or Smyd3) may into the gene regulatory regions (dashed lines). HMTs and HDMs can specifically target oncogenes, whereas those generating repres- regulate the expression of each other directly or indirectly (shown sive marks (for example, EZH2, G9a) would target tumor- an example of EZH2-miRNA-MMSET axis). Other layers of regulation involving histone modifications include effects on chromatin suppressor genes (Figure 1). compaction, genome stability and nuclear topology (right side). A novel type of regulation that involves crosstalk between two 103 Finally, HMTs and HDMs can modify non-histone proteins, like methylases has recently been revealed in prostate cancer cells. transcription factors, which modulate their DNA binding, protein EZH2, which mediates the repressive H3K27Me3 mark, functions stability or interaction with other proteins. Extensive crosstalks upstream of MMSET (NSD2), which catalyzes H3K36 dimethylation, between the different regulatory signals are discussed in the text.

Oncogene (2014) 1207 – 1217 & 2014 Macmillan Publishers Limited Context-specific regulation of cancer epigenomes M Sarris et al 1211 They belong to two major classes. The first class includes LSD1 with specific LSD1 inhibitors strongly inhibited proliferation, (KDM1A) and LSD2 (KDM1B), which are FAD -dependent independently of estrogen receptor status.133 Furthermore, LSD1 amine oxidases. The second class of enzymes is characterized by was found to interact with Snail and its activity was required for the presence of Jumonji C (JmjC) motif whose activity depends on Snail-mediated EMT of breast carcinoma.134 In each case, LSD1 Fe(II) and 2-oxoglutarate cofactors.105 functioned as a tumor-promoting factor, making it an ideal target The actual methylation status of histones is determined by the for anticancer drug development. interplay of methylases and demethylases. Given the important Contrasting this view is the recent report describing that LSD1 role of histone lysine methylation in cancer, it is expected that action inhibits the invasion of breast cancer cells in vitro similar to methyltransferases, deregulation of demethylases and suppresses breast cancer metastatic potential.106,135 This should also be involved in cancer development. Indeed, as shown effect was explained by the partitioning of LSD1 in the in Table 2, a variety of cancer phenotypes are associated with NURD corepressor complex, where it acts as an H3K4Me2 altered expression or activity of the different demethylating and represses key Tgfb1-regulated genes involved enzymes. in cell proliferation and epithelial to mesenchymal transition. LSD1 expression is deregulated in prostate, breast, colorectal, In agreement with this, LSD1 expression is reduced in metastatic lung and bladder cancer.105 LSD1 was first identified as breast carcinomas, negatively correlating with that of Tgfb1.106 a component of CoREST corepressor complex possessing Therefore, as seen with EZH2, it seems that LSD1 has either H3K4Me2 demethylase activity.129 Its role as a transcriptional oncogenic or tumor-suppressive functions, depending on a variety repressor seems to be gene specific, because it can change of factors such as the protein complex context, the type and the substrate specificity to catalyze H3K9Me1/2 demethylation when grade of the tumor, and the presence of other proteins or associated with the AR.130 Subsequent studies further refined the substrates directing LSD1 to different genomic regions. mechanism of LSD1 coactivator function, revealing that LSD1 acts Similar dual functioning in cancers has been described for the in concert with the JMJD2C (KDM4C) H3K9Me3 demethylase on H3K4 and H3K36 demethylase JHDM1B (FBXL10/KDM2B). JHDM1B AR target genes.131 Both enzymes are co-expressed at very high expression is decreased in aggressive brain tumors, where it has levels in prostate cancer and their expression correlates with the a tumor-suppressor role via controlling ribosomal RNA bio- aggressiveness of the tumors.132 The fact that small interfering genesis,112 whereas in other tumors, including adenocarcinomas RNA-mediated knockdown or inhibition of LSD1 activity in and lymphomas, JHDM1B is overexpressed.114 Its pro-oncogenic different cancer types always leads to cell cycle arrest and activity is achieved through a mechanism that involves repression apoptosis suggests that it operates as a coactivator or as a of Ink4b tumor-suppressor gene.136,137 corepressor in a highly specific manner on genes that induce or Overexpression of the H3K27 demethylase, JMJD3 (KDM6B), was suppress cell growth, respectively. Treatment of breast cancer cells detected in prostate cancer and Hodgkin’s lymphomas, where its

Table 2. Histone dimethylases

Gene Histone target Cancer type Abberation Ref

LSD1 (KDM1A) H3K4me1/2 Breast cancer Downregulation 106 H3K9me1/2 Breast cancer Overexpression 107 Bladder cancer Overexpression 108 Prostate cancer Overexpression 109 Colorectal cancer Overexpression 108 Small cell lung cancer Overexpression 108 Neuroblastoma Overexpression 110 HCC Low levels 111 JHDM1A (KDM2A) H3K36me2 Prostate cancer Downregulation 113 JHDM1B (KDM2B) H3K36me1/2 H3K4me3 Brain glioblastomas multiform Downregulation 112 Lymphomas Overexpression 114 JMJD1A (KDM3A) H3K9me1/2 Bladder and lung cancer Overexpression 115 JMJD2B (KDM4B) H3K36me2/3 H3K9me2/3 Gastric cancer Overexpression 116 JMJD2C (KDM4C) H3K36me2/3 H3K9me2/3 PMBL, HL Amplification in 9p24 117 chromosomal band Prostate cancer Overexpression 118 DMBs Genomic amplification 119 LSC Genomic amplification 120 JARID1A (KDM5A) H3K4me2/3 Gastric cancer Overexpression 121 JARID1B (KDM5B) H3K4me1/2/3 Prostate cancer Overexpression 122 Breast cancer Overexpression 123 JARID1C (KDM5C) H3K4me2/3 Renal cell carcinoma (ccRCC) Inactivating mutations 124 ccRCC Inactivating mutations 42 UTX (KDM6A) H3K27me2/3 Multiple myeloma Inactivating mutations 42 Esophageal squamous cell carcinomas Inactivating mutations 42 ccRCC Inactivating mutations 42 Multiple tumors Inactivating mutations 125 JMJD3 (KDM6B) H3K27me2/3 Prostate cancer Overexpression 126 Hodgkin’s lymphoma Overexpression 127 Lymphomas leukemias Downregulation 128 and other cancers Abbreviations: DMB, desmoplastic medulloblastoma; HCC, Hepatocellular carcinoma; HDM, histone dimethylase; HL, Hodgkin Lymphoma; LSC, lung sarcomatoid carcinoma; PMBL, primary mediastinal B-cell lymphoma.

& 2014 Macmillan Publishers Limited Oncogene (2014) 1207 – 1217 Context-specific regulation of cancer epigenomes M Sarris et al 1212 expression correlates with the derepression of proliferation these studies revealed a complex crosstalk between the different inducing genes.126,127 This enzyme has also the capacity to act methylated lysine residues, which also affects other modifications as a tumor suppressor via removing the repressive H3K27Me3 such as acetylations or ubiquitination of . Their interplay marks from the Ink4a/ARF locus, thereby activating the expression provides additional means of regulation, essential to fine tune the of the Ink4a tumor-suppressor gene.128,138 activity of the protein in different conditions. The H3K27 demethylase UTX (KDM6A) is another demethylase The multiplicity of p53 modifications and their cooperation for which context-specific opposite functioning has been coordinate diverse protein–protein interactions, which is reminis- described. Somatic inactivating mutations of UTX are common cent to those seen with histones. Direct parallel to mechanisms in a variety of cancers.42,125 In HPV16, E7 expressing cervical operating in histones is also illustrated by the crosstalk between cancer cells, however, UTX expression is induced and contributes methylation and other modifications of . E2F1 is methylated to the activation of Ink4A.139 by Set9 at K185, which promotes N-terminal ubiquitination and The above examples suggest that context-specific dual degradation of the protein.148 Methylated E2F1 is a poor substrate functioning of histone demethylases is a widespread phenom- of CHK2 and PCAF, and therefore, methylation prevents enon in different cancer types. It is likely that multiple mechan- phosphorylation and acetylation at distant residues, which isms are involved, which eventually should converge to effects of otherwise stabilize E2F1 during DNA damage conditions.148 The changing the actual histone methylation state of specific genes, crosstalk between the modifications operates in both directions as whose products stimulate or inhibit cell proliferation. One hyperacetylated or Ser364-phosphorylated E2F1 cannot be possibility is that the balanced action of certain methylases and methylated efficiently by Set9.147,148 LSD1 can demethylate K185 demethylases catalyzing the addition or removal of the same and leads to stabilization of the protein. Of particular interest is histone marks (for example, EZH2 and JMJD3 or UTX) on specific the opposite regulation of apoptosis mediated by E2F1 and p53 promoters may be affected differently in different cancer types. by the same set of enzymes. Set9-dependent methylation of E2F1 In this way the altered local equilibrium of the enzymatic actions destabilizes the protein and negatively influences E2F1-mediated may result in cell type-specific opposite effects. Such differences cell death, as opposed to its stabilizing function on p53, which should occur when genomic targeting of the enzymes is altered in promotes apoptosis. LSD1-mediated demethylation is required for different tumors. Identifying possible cooperations or antagonisms DNA damage-induced accumulation of E2F1 and activation of between the different histone-modifying enzymes, may shed light proapoptotic targets, whereas the enzymatic action of LSD1 into the mechanistic intricacies involved in establishing the inhibits p53 transcriptional activity. Therefore, cancer suppression dominance of tumor suppressing versus oncogenic function of approaches that combine DNA-damaging agents and drugs LSD1 and other demethylases. modulating LSD1 or Set9 activity may have inverse effects depending on the p53 status of the tumors. Further intricacies regarding transcription factor methylation- THE ROLE OF TRANSCRIPTION FACTOR MODIFICATION BY dependent control of cell cycle and tumor suppression was HISTONE LYSINE METHYLASES AND DEMETHYLASES IN revealed by the discovery of Set9-mediated methylation of the CARCINOGENESIS (Rb). Interestingly, Rb is methylated in two Histone modification-mediated modulation of chromatin structure distinct residues (K873 and K810) by Set9.149,150 Methylation at constitutes only part of the epigenetic mechanisms by which K873 creates a binding surface to HP1, whose association histone methylases and demethylases regulate gene expression. contributes to the transcriptional repressor function of Rb.149 In the past years, a plethora of studies identified other non-histone Methylation at K810 prevents CDK-dependent phosphorylations protein substrates, including transcription factors, whose activity is of nearby serine residues and the dissociation of Rb from regulated by methylation (Table 3). Since many of these E2F-bound promoters. Thus, Set9-mediated methylation of the transcription factors have direct roles in proliferation control, individual lysine residues affects different properties of Rb, but modulation of their activity by methylation may represent an both act as facilitators of Rb-mediated repression of proliferation- important layer of regulation of cancer-related processes. Indeed, associated genes and consequent cell cycle arrest. Rb is also several recent findings suggest that the importance of transcrip- subject to methylation by Smyd2 on K860 during cell cycle exit or tion factor methylation mechanisms in cancer may rival those DNA damage.162 This modification is recognized by L3MBTL1, involving histone modifications. which augments Rb-mediated gene repression. p53 is the best-studied non-histone substrate of histone NFkB can be methylated by Set9 at different residues. Like in methylases. p53 function is modulated differentially by methyla- the case of E2F1, methylation of K314 and K315 leads ubiquitina- tion of different lysine residues in its C-terminal unstructured tion and degradation of the protein,144 whereas methylation of domain. Set9(KMT7)-mediated mono-methylation of lysine 372 the N-terminal K37 positively regulates its promoter binding.145 results in the stabilization of chromatin-bound p53 and enhance- The opposite effects induced by the same enzyme through ment of activation of p53 target genes.142 Set9 can also modulate modification of different residues suggest that other factors p53 activity indirectly, through affecting SIRT1-p53 interaction should work in concert with Set9, which may modulate the and consequent deacetylation of p53.157 Smyd2-mediated configuration of NFkB substrate in a manner of assisting or monomethylation of K370, which has a repressive effect on p53 preventing one of the two modifications in specific conditions. , antagonizes K372 methylation.161 The K370 Another oncogenic protein target of Set9 is STAT3, which is residue is also subject to dimethylation, which is recognized by methylated at K140.146 STAT3 methylation occurs on the the DNA damage response protein 53BP1 via its Tudor domain. promoters of a subset of target genes and results in Dimethylation of K382 residue is another modification taking transcriptional repression.146 Unlike that of STAT3, the oncogenic place during DNA damage and this modification is also recognized function of estrogen receptor a is positively modulated by Set9. by 53BP1.171 The enzymes catalyzing 370 and 383 dimethylations Methylation of estrogen receptor a occurs at K302, which are not known. Interestingly, 53BP1 bound to K370Me2 acts as a stabilizes the protein and increases its sensitivity to estrogen coactivator of p53 target genes,172 while its association ligand.151 Interestingly, methylation of K302 is enhanced by a with K382Me2 is linked to DNA damage response signaling but breast cancer-associated mutation at K303 (K303R), suggesting not transcription.171 In the absence of DNA damage, p53 is that Set9 inhibitors may be beneficial for treating estrogen monomethylated at K382 by PR-SET7 and associates with receptor-positive aggressive breast tumors. L3MBTL1 leading to transcriptional repression.160 Dimethylation Set9-mediated methylation of the AR enhances its transcrip- of K373, mediated by G9a/Glp, also inactivates p53.168 Collectively, tional activity by facilitating inter-domain communication

Oncogene (2014) 1207 – 1217 & 2014 Macmillan Publishers Limited Context-specific regulation of cancer epigenomes M Sarris et al 1213 Table 3. Transcription factor methylases and demethylases

HMT HDM Substrate Effect Ref

Set9 (KMT7) TAF10 Pol-II association, transcription activation 140 LSD1 (KDM1A) p53 Protein stabilization 141,142 LSD1 NFkB Protein degradation 143,144 LSD1 Promoter binding, activation 145 Stat3 Repression of transcriptional activity 146 E2F1 Protein degradation 147,148 Rb HP1 interaction, transcription repression 149 Prevention of Cdk-mediated phosphorylation 150 ERa Protein stabilization 151 AR Interdomain interaction, transcription activation 152,153 DNMT1 Protein degradation 154–156 Sirt1 Unknown 157 Foxo3 Inhibition of DNA binding, transactivation 158 Protein degradation 159

PR-SET7 (KMT5A) P53 Repression of transcriptional activity 160 Smyd2 (KMT3C) LSD1 P53 Repression of transcriptional activity 161 Rb LMBTL1 interaction, repression 162 SetD6 NFkB GLP interaction 163 NSD1 (KMT3B) JHDM1A (KDM2A) NFkB Increased transcriptional activity 164 G9a (KMT1C) MyoD Repression of transcriptional activity 165 C/EBPb Repression of transcriptional activity 166 G9a Interaction with HP1 167 P53 Inactivation of P53 168 Suv39H1 (KMT1A) PC2 ncRNA interaction, subnuclear repositioning 169 EZH2 (KMT6) RoRa Protein degradation 170 Abbreviations: AR, androgen receptor; NF, nuclear factor; ncRNA, non-coding RNA; Rb, retinoblastoma protein. between the N- and the C-terminus of the protein and stimulates On the other hand, the chromatin modification function of the AR recruitment to androgen-dependent target genes.152,153 In this other transcription factor methylases, like Smyd2, PR-SET7 or G9a, way, Set9 displays a pro-proliferative and antiapoptotic role in is well established. Examining their function on histones or prostate cancer cells. Set9 expression is upregulated in epithelial transcription factors, it is evident that in the case of concurrent cells and concurrently downregulated in stromal cells of prostate operation, synergistic effects are expected. For example, a pro- cancer, suggesting that deregulation of SET9 expression may have oncogenic outcome is expected either through Smyd2-mediated an important role in driving uncontrolled growth of androgen- positioning of activatory histone modification marks on prolifera- dependent prostate cancer cells.152,153 Through the specific action tion-associated genes or via its negative modulatory effects on of LSD1, both STAT3 and AR-mediated methylation are reversible. tumor suppressors Rb or p53. The same is signified by PR-SET7 Interesting and pertinent to controlling cancer growth is function, which safeguards the integrity of the genome by the Suv39H1-mediated methylation of PC2 protein.169 PC2 methylating H4K20 at heterochromatin regions and by preventing methylation is responsible for the physical relocation of E2F1- apoptosis induction by methylating p53 and keeping it inactive in bound S-phase-specific genes from polycomb (PcG) bodies, where the absence of DNA damage. their expression is repressed, to interchromatin granules, where Corroborating the above principle is the recently identified their expression is activated.169 This is driven by the differential transcription factor methylation function of EZH2. EZH2 can interactions of methylated versus unmethylated Pc2 with two methylate the tumor-suppressor RORa and distinct non-coding RNAs that are located in distinct subnuclear triggers its degradation via the recruitment of DCAF1/DDB1 compartments.169 The findings suggest that methylated Pc2 may CUL4 E3 ubiquitin complex.170 The methylation-dependent represent an important antimitogenic signal and functions as a degradation of another tumor-suppressor protein, such as RORa, stress-induced modification mark required for the repression of augments the well known oncogenic function of EZH2, which is growth-related genes and the senescent phenotype, whereas realized through the placement of the repressive H3K27 unmethylated Pc2 is essential for physiological cell proliferation. methylation marks on INK4A-ARF tumor-suppressor locus or on miR203, miR26 and miR31 genes. Direct crosstalk between protein and histone methylation that INTERPLAY BETWEEN TRANSCRIPTION FACTOR AND HISTONE regulates transcriptional outputs was revealed by studies on the METHYLATION FUNCTION role of posttranslational modifications of NFkB in gene activation. Most of the non-histone proteins listed in Table 3 are methylated Setd6-mediated methylation of RelA K310 facilitates the recruit- by Set9. Although Set9 was originally identified as an H3K4 ment of another histone methylase GLP, which in turn methylates monomethylase, its role in chromatin modification is not well H3K9 at the underlining nucleosomes and promotes repressed understood. Set9 cannot methylate nucleosomal histones in vitro, chromatin states.163 Phosphorylation of RelA by PKCz blocks which led to the view that Set9 is mainly a factor methylase and binding of GLP to methylated K310 and relieves repression of not a chromatin modifier in vivo. Subsequently, however, it was target genes.163 demonstrated that on SWI/SNF-remodeled nucleosomes, Set9 is a potent histone methylase.173 Thus, although direct evidence for the role of Set9-mediated histone modification on gene regulatory CONCLUDING REMARKS regions is still missing, its function on chromatin structure cannot Taken together, numerous studies during the past years, estab- be entirely excluded. lished the view that histone lysine methylases and demethylases

& 2014 Macmillan Publishers Limited Oncogene (2014) 1207 – 1217 Context-specific regulation of cancer epigenomes M Sarris et al 1214 are key components of the regulatory protein complexes involved 15 Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC et al. The genetic landscape in the orchestration of spatial and temporal patterns of gene of the childhood cancer medulloblastoma. Science 2011; 331: 435–439. expression and chromosomal integrity. They function in a broad 16 Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD et al. range of biological processes via modification of chromatin or Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. DNA-binding transcription factors and via dynamic positioning of Nature 2011; 476: 298–303. genes to particular loci in the nucleus. Cancer-specific alteration of 17 McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y et al. Mutation of their expression, or activity affects the above processes in several A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes ways (Figure 1). They usually lead to defects affecting the complex hypertrimethylation of on lysine 27 (H3K27). Proc Natl Acad Sci USA 2012; 109: 2989–2994. interplay between histone modifications at different genes and to 18 Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R et al. Somatic defects, affecting the activities of transcription factors, which mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas regulate cell proliferation and genome integrity. In several cases, of germinal-center origin. Nat Genet 2010; 42: 181–185. altered activities of histone lysine-modifying enzymes exhibit 19 Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV et al. Inactivating cellular context-specific opposite effects on growth regulation. This mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat is not surprising, given the complexity of their effects on different Genet 2010; 42: 722–726. target genes. Complexity comes from crosstalks between different 20 Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA et al. EZH2 is a marker of histone modifications and different transcription factors or proteins aggressive breast cancer and promotes neoplastic transformation of breast involved in nuclear organization of the genome. Precise operation epithelial cells. Proc Natl Acad Sci USA 2003; 100: 11606–11611. 21 Collett K, Eide GE, Arnes J, Stefansson IM, Eide J, Braaten A et al. Expression of of these different regulatory layers is pivotal to achieve a tightly enhancer of zeste homologue 2 is significantly associated with increased tumor coordinated epigenomic programming of DNA-templated pro- cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res cesses (Figure 1). 2006; 12: 1168–1174. Future research aimed at the functional dissection of the above 22 Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K et al. regulatory layers in the context of different cancers holds promise Expression levels of the EZH2 polycomb transcriptional repressor correlate with to uncover unexpected molecular modes of epigenetic actions aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 2005; with far-reaching benefits for the design of novel therapeutic 16: 349–353. approaches. 23 Saramaki OR, Tammela TL, Martikainen PM, Vessella RL, Visakorpi T. The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer. Genes Cancer 2006; 45: 639–645. 24 Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B et al. Genomic loss of CONFLICT OF INTEREST microRNA-101 leads to overexpression of histone methyltransferase EZH2 in The authors declare no conflict of interest. cancer. Science 2008; 322: 1695–1699. 25 Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG et al. The polycomb group protein EZH2 is involved in progression of prostate ACKNOWLEDGEMENTS cancer. Nature 2002; 419: 624–629. 26 Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA et al. Work in the author’s lab is supported by European Research Council Advanced EZH2 expression is associated with high proliferation rate and aggressive tumor Investigator Grant (ERC-2011-AdG294464) and the Greek Operational Program subgroups in cutaneous melanoma and cancers of the endometrium, prostate, ‘Education and Lifelong Learning’ of the National Strategic Reference Framework and breast. JClinOncol2006; 24:268–273. (NSRF)—Research Funding Program: Thales (Thales 656). 27 van Kemenade FJ, Raaphorst FM, Blokzijl T, Fieret E, Hamer KM, Satijn DP et al. Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood REFERENCES 2001; 97: 3896–3901. 1 Kouzarides T. Chromatin modifications and their function. Cell 2007; 128: 28 Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF et al. MYC 693–705. stimulates EZH2 expression by repression of its negative regulator miR-26a. 2 Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293: 1074–1080. Blood 2008; 112: 4202–4212. 3 Esteller M. Cancer epigenomics: DNA methylomes and histone-modification 29 Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by maps. Nat Rev Genet 2007; 8: 286–298. mediating histone H3 methylation in gastric cancer cells. Cancer Sci 2008; 99: 4 Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during 738–746. development and disease pathogenesis. Nat Struct Mol Biol 2007; 14: 1008–1016. 30 Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y et al. Alterations of 5 Berger SL. The complex language of chromatin regulation during transcription. DNA methylation and histone modifications contribute to gene silencing in Nature 2007; 447: 407–412. hepatocellular carcinomas. Hepatol Res 2007; 37: 974–983. 6 Trojer P, Reinberg D. Facultative heterochromatin: is there a distinctive 31 Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K et al. A novel gene, molecular signature? Mol Cell 2007; 28: 1–13. NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute 7 Vermeulen M, Mulder KW, Denissov S, Pijnappel WW, van Schaik FM, Varier RA et al. myeloid leukemia. Blood 2001; 98: 1264–1267. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 32 Cerveira N, Correia C, Doria S, Bizarro S, Rocha P, Gomes P et al. Frequency of 4. Cell 2007; 131:58–69. NUP98-NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 8 Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 2003; 17: 2244–2247. lysine 9 creates a for HP1 proteins. Nature 2001; 410: 116–120. 33 Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S et al. Genotype- 9 Albert M, Helin K. Histone methyltransferases in cancer. Semin Cell Dev Biol 2010; phenotype associations in Sotos syndrome: an analysis of 266 individuals with 21: 209–220. NSD1 aberrations. Am J Hum Genet 2005; 77: 193–204. 10 Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by 34 Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, Losson R et al. Epigenetic MLL fusion proteins. Oncogene 2001; 20: 5695–5707. inactivation of the Sotos overgrowth syndrome gene histone methyltransferase 11 Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci USA 2009; 106: leukaemia stem-cell development. Nat Rev Cancer 2007; 7: 823–833. 21830–21835. 12 Dorrance AM, Liu S, Chong A, Pulley B, Nemer D, Guimond M et al. The Mll partial 35 Kassambara A, Klein B, Moreaux J. MMSET is overexpressed in cancers: link with tandem duplication: differential, tissue-specific activity in the presence or tumor aggressiveness. Biochem Biophys Res Commun 2009; 379: 840–845. absence of the wild-type allele. Blood 2008; 112: 2508–2511. 36 Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiaer E, Rossing HH, Johansen JV 13 Dorrance AM, Liu S, Yuan W, Becknell B, Arnoczky KJ, Guimond M et al. Mll partial et al. The histone methyltransferase and putative oncoprotein MMSET is tandem duplication induces aberrant Hox expression in vivo via specific overexpressed in a large variety of human tumors. Clin Cancer Res 2011; 17: epigenetic alterations. J Clin Invest 2006; 116: 2707–2716. 2919–2933. 14 Whitman SP, Hackanson B, Liyanarachchi S, Liu S, Rush LJ, Maharry K et al. DNA 37 Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM et al. Frequent hypermethylation and epigenetic silencing of the tumor suppressor gene, translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication. increased expression and activating mutations of fibroblast growth factor Blood 2008; 112: 2013–2016. receptor 3. Nat Genet 1997; 16: 260–264.

Oncogene (2014) 1207 – 1217 & 2014 Macmillan Publishers Limited Context-specific regulation of cancer epigenomes M Sarris et al 1215 38 Malgeri U, Baldini L, Perfetti V, Fabris S, Vignarelli MC, Colombo G et al. Detection 62 Steele-Perkins G, Fang W, Yang XH, Van Gele M, Carling T, Gu J et al. of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by reverse Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear transcription-polymerase chain reaction analysis of IGH-MMSET fusion tran- protein-methyltransferase superfamily. Genes Dev 2001; 15: 2250–2262. scripts. Cancer Res 2000; 60: 4058–4061. 63 Oshimo Y, Oue N, Mitani Y, Nakayama H, Kitadai Y, Yoshida K et al. Frequent 39 Rosati R, La Starza R, Veronese A, Aventin A, Schwienbacher C, Vallespi T et al. epigenetic inactivation of RIZ1 by promoter hypermethylation in human gastric NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with carcinoma. Int J Cancer 2004; 110: 212–218. t(8;11)(p11.2;p15). Blood 2002; 99: 3857–3860. 64 Tokumaru Y, Nomoto S, Jeronimo C, Henrique R, Harden S, Trink B et al. Biallelic 40 Angrand PO, Apiou F, Stewart AF, Dutrillaux B, Losson R, Chambon P. NSD3 a inactivation of the RIZ1 gene in human gastric cancer. Oncogene 2003; 22: new SET domain-containing gene, maps to 8p12 and is amplified in human 6954–6958. breast cancer cell lines. Genomics 2001; 74: 79–88. 65 Piao GH, Piao WH, He Y, Zhang HH, Wang GQ, Piao Z. Hyper-methylation of RIZ1 41 Duns G, van den Berg E, van Duivenbode I, Osinga J, Hollema H, Hofstra RM et al. tumor suppressor gene is involved in the early tumorigenesis of hepatocellular Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear carcinoma. Histol Histopathol 2008; 23: 1171–1175. cell renal cell carcinoma. Cancer Res 2010; 70: 4287–4291. 66 Jiang G, Liu L, Buyse IM, Simon D, Huang S. Decreased RIZ1 expression but not 42 Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A et al. Systematic RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1. sequencing of renal carcinoma reveals inactivation of histone modifying genes. Int J Cancer 1999; 83: 541–546. Nature 2010; 463: 360–363. 67 Deng Q, Huang S. PRDM5 is silenced in human cancers and has growth 43 Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C et al. Loss of suppressive activities. Oncogene 2004; 23: 4903–4910. the Suv39h histone methyltransferases impairs mammalian heterochromatin 68 Watanabe Y, Toyota M, Kondo Y, Suzuki H, Imai T, Ohe-Toyota M et al. PRDM5 and genome stability. Cell 2001; 107: 323–337. identified as a target of epigenetic silencing in colorectal and gastric cancer. 44 Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S et al. Multiple Clin Cancer Res 2007; 13: 4786–4794. recurrent genetic events converge on control of histone lysine methylation in 69 Kolomietz E, Marrano P, Yee K, Thai B, Braude I, Kolomietz A et al. Quantitative medulloblastoma. Nat Genet 2009; 41: 465–472. PCR identifies a minimal deleted region of 120 kb extending from the Phila- 45 Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V et al. The delphia chromosome ABL translocation breakpoint in chronic myeloid leukemia histone methyltransferase SETDB1 is recurrently amplified in melanoma and with poor outcome. Leukemia 2003; 17: 1313–1323. accelerates its onset. Nature 2011; 471: 513–517. 70 Reid AG, Nacheva EP. A potential role for PRDM12 in the pathogenesis of chronic 46 Skawran B, Steinemann D, Weigmann A, Flemming P, Becker T, Flik J et al. Gene myeloid leukaemia with derivative chromosome 9 deletion. Leukemia 2004; 18: expression profiling in hepatocellular carcinoma: upregulation of genes in 178–180. amplified chromosome regions. Mod Pathol 2008; 21: 505–516. 71 Nishikawa N, Toyota M, Suzuki H, Honma T, Fujikane T, Ohmura T et al. Gene 47 Komatsu S, Imoto I, Tsuda H, Ki Kozaki, Muramatsu T, Shimada Y et al. amplification and overexpression of PRDM14 in breast cancers. Cancer Res 2007; Overexpression of SMYD2 relates to tumor cell proliferation and malignant 67: 9649–9657. outcome of esophageal squamous cell carcinoma. Carcinogenesis 2009; 30: 72 Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R et al. ALL-1 is a 1139–1146. histone methyltransferase that assembles a supercomplex of proteins involved 48 Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M et al. SMYD3 in transcriptional regulation. Mol Cell 2002; 10: 1119–1128. encodes a histone methyltransferase involved in the proliferation of cancer cells. 73 Mueller D, Bach C, Zeisig D, Garcia-Cuellar MP, Monroe S, Sreekumar A et al. Nat Cell Biol 2004; 6: 731–740. A role for the MLL fusion partner ENL in transcriptional elongation and chro- 49 Hamamoto R, Silva FP, Tsuge M, Nishidate T, Katagiri T, Nakamura Y et al. matin modification. Blood 2007; 110: 4445–4454. Enhanced SMYD3 expression is essential for the growth of breast cancer cells. 74 Lin YH, Kakadia PM, Chen Y, Li YQ, Deshpande AJ, Buske C et al. Global reduction Cancer Sci 2006; 97: 113–118. of the epigenetic H3K79 methylation mark and increased chromosomal 50 Hu L, Zhu YT, Qi C, Zhu YJ. Identification of Smyd4 as a potential tumor instability in CALM-AF10-positive leukemias. Blood 2009; 114: 651–658. suppressor gene involved in breast cancer development. Cancer Res 2009; 69: 75 Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M et al. NSD1 4067–4072. mutations are the major cause of Sotos syndrome and occur in some cases of 51 Takawa M, Cho HS, Hayami S, Toyokawa G, Kogure M, Yamane Y et al. Histone Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA Genet 2003; 72: 132–143. expression. Cancer Res 2012; 72: 3217–3227. 76 Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T et al. Haplo- 52 Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM et al. hDOT1L links histone insufficiency of NSD1 causes Sotos syndrome. Nat Genet 2002; 30: 365–366. methylation to leukemogenesis. Cell 2005; 121: 167–178. 77 Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L et al. 53 Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU et al. H3K79 The MMSET histone methyl switches global histone methylation and methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell alters gene expression in t(4;14) multiple myeloma cells. Blood 2011; 117: 2008; 14: 355–368. 211–220. 54 Okada Y, Jiang Q, Lemieux M, Jeannotte L, Su L, Zhang Y. Leukaemic transfor- 78 Liu C, Fang X, Ge Z, Jalink M, Kyo S, Bjorkholm M et al. The telomerase reverse mation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nat Cell Biol transcriptase (hTERT) gene is a direct target of the histone methyltransferase 2006; 8: 1017–1024. SMYD3. Cancer Res 2007; 67: 2626–2631. 55 Tam W, Gomez M, Chadburn A, Lee JW, Chan WC, Knowles DM. Mutational 79 Kim H, Heo K, Kim JH, Kim K, Choi J, An W. Requirement of histone methyl- analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell transferase SMYD3 for estrogen receptor-mediated transcription. J Biol Chem lymphomas. Blood 2006; 107: 4090–4100. 2009; 284: 19867–19877. 56 Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A, Nandula SV et al. 80 Cock-Rada AM, Medjkane S, Janski N, Yousfi N, Perichon M, Chaussepied M et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp SMYD3 promotes cancer invasion by epigenetic upregulation of the metallo- Med 2006; 203: 311–317. proteinase MMP-9. Cancer Res 2012; 72: 810–820. 57 Nie K, Gomez M, Landgraf P, Garcia JF, Liu Y, Tan LH et al. MicroRNA-mediated 81 Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, Shimada Y et al. Over- down-regulation of PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg cells: a potential expression of SMYD2 relates to tumor cell proliferation and malignant outcome pathogenetic lesion in Hodgkin lymphomas. Am J Pathol 2008; 173: 242–252. of esophageal squamous cell carcinoma. Carcinogenesis 2009; 30: 1139–1146. 58 Courts C, Montesinos-Rongen M, Brunn A, Bug S, Siemer D, Hans V et al. 82 Brown MA, Sims 3rd RJ, Gottlieb PD, Tucker PW. Identification and character- Recurrent inactivation of the PRDM1 gene in primary central nervous system ization of Smyd2: a split SET/MYND domain-containing histone H3 lysine lymphoma. J Neuropathol Exp Neurol 2008; 67: 720–727. 36-specific methyltransferase that interacts with the Sin3 histone deacetylase 59 He L, Yu JX, Liu L, Buyse IM, Wang MS, Yang QC et al. RIZ1, but not the alternative complex. Mol Cancer 2006; 5:26. RIZ2 product of the same gene, is underexpressed in breast cancer, and forced 83 Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis. Cancer Res 1998; tale of two domains: proteomics and genomics analysis of SMYD2, a new histone 58: 4238–4244. methyltransferase. Mol Cell Proteomics 2008; 7: 560–572. 60 Du Y, Carling T, Fang W, Piao Z, Sheu JC, Huang S. Hypermethylation in human 84 Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y et al. cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of methyltransferase superfamily. Cancer Res 2001; 61: 8094–8099. histone H4 and is associated with silent chromatin. Mol Cell 2002; 9: 1201–1213. 61 Chadwick RB, Jiang GL, Bennington GA, Yuan B, Johnson CK, Stevens MW et al. 85 Rice JC, Nishioka K, Sarma K, Steward R, Reinberg D, Allis CD. Mitotic-specific Candidate tumor suppressor RIZ is frequently involved in colorectal carcino- methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its genesis. Proc Natl Acad Sci USA 2000; 97: 2662–2667. localization to mitotic chromosomes. Genes Dev 2002; 16: 2225–2230.

& 2014 Macmillan Publishers Limited Oncogene (2014) 1207 – 1217 Context-specific regulation of cancer epigenomes M Sarris et al 1216 86 Oda H, Hubner MR, Beck DB, Vermeulen M, Hurwitz J, Spector DL et al. 110 Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R et al. Lysine- Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)- specific demethylase 1 is strongly expressed in poorly differentiated neuro- mediated PCNA-dependent degradation during DNA damage. Mol Cell 2010; 40: blastoma: implications for therapy. Cancer Res 2009; 69: 2065–2071. 364–376. 111 Magerl C, Ellinger J, Braunschweig T, Kremmer E, Koch LK, Holler T et al. H3K4 87 Oda H, Okamoto I, Murphy N, Chu J, Price SM, Shen MM et al. Monomethylation dimethylation in hepatocellular carcinoma is rare compared with other hepa- of histone H4-lysine 20 is involved in chromosome structure and stability and is tobiliary and gastrointestinal carcinomas and correlates with expression of the essential for mouse development. Mol Cell Biol 2009; 29: 2278–2295. methylase Ash2 and the demethylase LSD1. Hum Pathol 2010; 41: 181–189. 88 Beck DB, Burton A, Oda H, Ziegler-Birling C, Torres-Padilla ME, Reinberg D. The 112 Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M. JHDM1B/ role of PR-Set7 in replication licensing depends on Suv4–20h. Genes Dev 2012; FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA 26: 2580–2589. genes. Nature 2007; 450: 309–313. 89 Wu S, Wang W, Kong X, Congdon LM, Yokomori K, Kirschner MW et al. Dynamic 113 Frescas D, Guardavaccaro D, Kuchay SM, Kato H, Poleshko A, Basrur V et al. regulation of the PR-Set7 histone methyltransferase is required for normal cell KDM2A represses transcription of centromeric satellite repeats and maintains cycle progression. Genes Dev 2010; 24: 2531–2542. the heterochromatic state. Cell Cycle 2008; 7: 3539–3547. 90 Yang F, Sun L, Li Q, Han X, Lei L, Zhang H et al. SET8 promotes epithelial- 114 Pfau R, Tzatsos A, Kampranis SC, Serebrennikova OB, Bear SE, Tsichlis PN. mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J Members of a family of JmjC domain-containing oncoproteins immortalize 2012; 31: 110–123. embryonic fibroblasts via a JmjC domain-dependent process. Proc Natl Acad Sci 91 Towbin BD, Gonzalez-Aguilera C, Sack R, Gaidatzis D, Kalck V, Meister P et al. USA 2008; 105: 1907–1912. Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear 115 Cho HS, Toyokawa G, Daigo Y, Hayami S, Masuda K, Ikawa N et al. The JmjC periphery. Cell 2012; 150: 934–947. domain-containing histone demethylase KDM3A is a positive regulator of the 92 O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. The poly- G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene. comb-group gene Ezh2 is required for early mouse development. Mol Cell Biol Int J Cancer 2012; 131: E179–E189. 2001; 21: 4330–4336. 116 Li W, Zhao L, Zang W, Liu Z, Chen L, Liu T et al. Histone demethylase JMJD2B is 93 Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, required for tumor cell proliferation and survival and is overexpressed in gastric Beekman C et al. The polycomb group proteins bind throughout the INK4A-ARF cancer. Biochem Biophys Res Commun 2011; 416: 372–378. locus and are disassociated in senescent cells. Genes Dev 2007; 21: 525–530. 117 Rui L, Emre NC, Kruhlak MJ, Chung HJ, Steidl C, Slack G et al. Cooperative 94 Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J et al. Bypass epigenetic modulation by cancer amplicon genes. Cancer Cell 2010; 18: 590–605. of senescence by the polycomb group protein CBX8 through direct binding to 118 Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T et al. The the INK4A-ARF locus. EMBO J 2007; 26: 1637–1648. putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on 95 Beke L, Nuytten M, Van Eynde A, Beullens M, Bollen M. The gene encoding the histone H3. Nature 2006; 442: 307–311. prostatic tumor suppressor PSP94 is a target for repression by the Polycomb 119 Ehrbrecht A, Muller U, Wolter M, Hoischen A, Koch A, Radlwimmer B et al. group protein EZH2. Oncogene 2007; 26: 4590–4595. Comprehensive genomic analysis of desmoplastic medulloblastomas: identifi- 96 Yu J, Cao Q, Mehra R, Laxman B, Tomlins SA, Creighton CJ et al. Integrative cation of novel amplified genes and separate evaluation of the different histo- genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in logical components. J Pathol 2006; 208: 554–563. prostate cancer. Cancer Cell 2007; 12: 419–431. 120 Italiano A, Attias R, Aurias A, Perot G, Burel-Vandenbos F, Otto J et al. Molecular 97 Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH et al. Epigenetic-mediated cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 dysfunction of the bone morphogenetic protein pathway inhibits differentiation neocentromere and 9p23-p24 amplification including JAK2 and JMJD2C. Cancer of glioblastoma-initiating cells. Cancer Cell 2008; 13: 69–80. Genet Cytogenet 2006; 167: 122–130. 98 Gonzalez ME, DuPrie ML, Krueger H, Merajver SD, Ventura AC, Toy KA et al. 121 Zeng J, Ge Z, Wang L, Li Q, Wang N, Bjorkholm M et al. The histone demethylase Histone methyltransferase EZH2 induces Akt-dependent genomic instability and RBP2 Is overexpressed in gastric cancer and its inhibition triggers senescence of BRCA1 inhibition in breast cancer. Cancer Res 2011; 71: 2360–2370. cancer cells. Gastroenterology 2010; 138: 981–992. 99 Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA et al. Repression of 122 Xiang Y, Zhu Z, Han G, Ye X, Xu B, Peng Z et al. JARID1B is a histone H3 lysine E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008; 27: 4 demethylase up-regulated in prostate cancer. Proc Natl Acad Sci USA 2007; 7274–7284. 104: 19226–19231. 100 Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream 123 Lu PJ, Sundquist K, Baeckstrom D, Poulsom R, Hanby A, Meier-Ewert S et al. of the pRB-E2F pathway, essential for proliferation and amplified in cancer. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin EMBO J 2003; 22: 5323–5335. binding motifs is specifically up-regulated in breast cancer. J Biol Chem 1999; 101 Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK et al. Context-specific regulation of 274: 15633–15645. NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell 2011; 43: 124 Niu X, Zhang T, Liao L, Zhou L, Lindner DJ, Zhou M et al. The von Hippel-Lindau 798–810. tumor suppressor protein regulates gene expression and tumor growth through 102 Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT et al. EZH2 oncogenic activity in histone demethylase JARID1C. Oncogene 2012; 31: 776–786. castration-resistant prostate cancer cells is Polycomb-independent. Science 2012; 125 van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C et al. 338: 1465–1469. Somatic mutations of the histone H3K27 demethylase gene UTX in human 103 Asangani IA, Ateeq B, Cao Q, Dodson L, Pandhi M, Kunju LP et al. Character- cancer. Nat Genet 2009; 41: 521–523. ization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. 126 Xiang Y, Zhu Z, Han G, Lin H, Xu L, Chen CD. JMJD3 is a histone H3K27 Mol Cell 2012; 49: 80–93. demethylase. Cell Res 2007; 17: 850–857. 104 Zuber J, Rappaport AR, Luo W, Wang E, Chen C, Vaseva AV et al. An integrated 127 Anderton JA, Bose S, Vockerodt M, Vrzalikova K, Wei W, Kuo M et al. The approach to dissecting oncogene addiction implicates a Myb-coordinated self- H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over- renewal program as essential for leukemia maintenance. Genes Dev 2011; 25: expressed in Hodgkin’s Lymphoma. Oncogene 2011; 30: 2037–2043. 1628–1640. 128 Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J et al. The 105 Pedersen MT, Helin K. Histone demethylases in development and disease. Trends H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF Cell Biol 2010; 20: 662–671. locus in response to oncogene- and stress-induced senescence. Genes Dev 2009; 106 Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W et al. LSD1 is a subunit of the 23: 1171–1176. NuRD complex and targets the metastasis programs in breast cancer. Cell 2009; 129 Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA et al. Histone deme- 138: 660–672. thylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004; 119: 107 Lim S, Janzer A, Becker A, Zimmer A, Schule R, Buettner R et al. Lysine-specific 941–953. demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers 130 Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH et al. LSD1 and a biomarker predicting aggressive biology. Carcinogenesis 2010; 31: demethylates repressive histone marks to promote androgen-receptor-depen- 512–520. dent transcription. Nature 2005; 437: 436–439. 108 Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T et al. Over- 131 Wissmann M, Yin N, Muller JM, Greschik H, Fodor BD, Jenuwein T et al. expression of LSD1 contributes to human carcinogenesis through chromatin Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor- regulation in various cancers. Int J Cancer 2011; 128: 574–586. dependent gene expression. Nat Cell Biol 2007; 9: 347–353. 109 Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R et al. Androgen 132 Kauffman EC, Robinson BD, Downes MJ, Powell LG, Lee MM, Scherr DS et al. Role receptor coactivators lysine-specific histone demethylase 1 and four and a half of androgen receptor and associated lysine-demethylase coregulators, LSD1 and LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res 2006; JMJD2A, in localized and advanced human bladder cancer. Mol Carcinog 2011; 66: 11341–11347. 50: 931–944.

Oncogene (2014) 1207 – 1217 & 2014 Macmillan Publishers Limited Context-specific regulation of cancer epigenomes M Sarris et al 1217 133 Pollock JA, Larrea MD, Jasper JS, McDonnell DP, McCafferty DG. Lysine-specific 154 Esteve PO, Chang Y, Samaranayake M, Upadhyay AK, Horton JR, Feehery GR et al. histone demethylase 1 inhibitors control breast cancer proliferation in A methylation and phosphorylation switch between an adjacent lysine and ERalpha-dependent and -independent manners. ACS Chem Biol 2012; 7: serine determines human DNMT1 stability. Nat Struct Mol Biol 2011; 18: 42–48. 1221–1231. 155 Esteve PO, Chin HG, Benner J, Feehery GR, Samaranayake M, Horwitz GA et al. 134 Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI et al. The SNAG domain of Snail1 functions Regulation of DNMT1 stability through SET7-mediated lysine methylation in as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J 2010; mammalian cells. Proc Natl Acad Sci USA 2009; 106: 5076–5081. 29: 1803–1816. 156 Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J et al. The lysine demethylase LSD1 135 Li Q, Shi L, Gui B, Yu W, Wang J, Zhang D et al. Binding of the JmjC demethylase (KDM1) is required for maintenance of global DNA methylation. Nat Genet 2009; JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer 41: 125–129. cells by repressing chemokine CCL14. Cancer Res 2011; 71: 6899–6908. 157 Liu X, Wang D, Zhao Y, Tu B, Zheng Z, Wang L et al. Methyltransferase Set7/9 136 He J, Kallin EM, Tsukada Y, Zhang Y. The H3K36 demethylase Jhdm1b/Kdm2b regulates p53 activity by interacting with Sirtuin 1 (SIRT1). Proc Natl Acad Sci USA regulates cell proliferation and senescence through p15(Ink4b). Nat Struct Mol 2011; 108: 1925–1930. Biol 2008; 15: 1169–1175. 158 Xie Q, Hao Y, Tao L, Peng S, Rao C, Chen H et al. Lysine methylation of 137 Tzatsos A, Pfau R, Kampranis SC, Tsichlis PN. Ndy1/KDM2B immortalizes mouse FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Rep 2012; embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci USA 13: 371–377. 2009; 106: 2641–2646. 159 Calnan DR, Webb AE, White JL, Stowe TR, Goswami T, Shi X et al. Methylation by 138 Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenfuhr M et al. Set9 modulates FoxO3 stability and transcriptional activity. Aging (Albany NY) Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by 2012; 4: 462–479. oncogenic RAS. Genes Dev 2009; 23: 1177–1182. 160 Shi X, Kachirskaia I, Yamaguchi H, West LE, Wen H, Wang EW et al. Modulation of 139 McLaughlin-Drubin ME, Crum CP, Munger K. Human papillomavirus p53 function by SET8-mediated methylation at lysine 382. Mol Cell 2007; 27: E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression 636–646. and causes epigenetic reprogramming. Proc Natl Acad Sci USA 2011; 108: 161 Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA et al. 2130–2135. Repression of p53 activity by Smyd2-mediated methylation. Nature 2006; 444: 140 Kouskouti A, Scheer E, Staub A, Tora L, Talianidis I. Gene-specific modulation of 629–632. TAF10 function by SET9-mediated methylation. Mol Cell 2004; 14: 175–182. 162 Saddic LA, West LE, Aslanian A, Yates 3rd JR, Rubin SM, Gozani O et al. 141 Ivanov GS, Ivanova T, Kurash J, Ivanov A, Chuikov S, Gizatullin F et al. Methyla- Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem tion-acetylation interplay activates p53 in response to DNA damage. Mol Cell Biol 2010; 285: 37733–37740. 2007; 27: 6756–6769. 163 Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P et al. Lysine methylation 142 Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS et al. Regulation of of the NF-kappaB subunit RelA by SETD6 couples activity of the histone p53 activity through lysine methylation. Nature 2004; 432: 353–360. methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. 143 Yang XD, Tajkhorshid E, Chen LF. Functional interplay between acetylation Nat Immunol 2011; 12:29–36. and methylation of the RelA subunit of NF-kappaB. Mol Cell Biol 2010; 30: 164 Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M et al. Regulation of 2170–2180. NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. 144 Yang XD, Huang B, Li M, Lamb A, Kelleher NL, Chen LF. Negative regulation of Proc Natl Acad Sci USA 2010; 107: 46–51. NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit. 165 Ling BM, Bharathy N, Chung TK, Kok WK, Li S, Tan YH et al. Lysine methyl- EMBO J 2009; 28: 1055–1066. transferase G9a methylates the transcription factor MyoD and regulates skeletal 145 Ea CK, Baltimore D. Regulation of NF-kappaB activity through lysine mono- muscle differentiation. Proc Natl Acad Sci USA 2012; 109: 841–846. methylation of p65. Proc Natl Acad Sci USA 2009; 106: 18972–18977. 166 Pless O, Kowenz-Leutz E, Knoblich M, Lausen J, Beyermann M, Walsh MJ et al. 146 Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B et al. Reversible G9a-mediated lysine methylation alters the function of CCAAT/enhancer- methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl binding protein-beta. J Biol Chem 2008; 283: 26357–26363. Acad Sci USA 2010; 107: 21499–21504. 167 Sampath SC, Marazzi I, Yap KL, Krutchinsky AN, Mecklenbrauker I, Viale A et al. 147 Kontaki H, Talianidis I. Cross-talk between post-translational modifications Methylation of a histone mimic within the histone methyltransferase G9a regulate life or death decisions by E2F1. Cell Cycle 2010; 9: 3836–3837. regulates protein complex assembly. Mol Cell 2007; 27: 596–608. 148 Kontaki H, Talianidis I. Lysine methylation regulates E2F1-induced cell death. 168 Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T et al. G9a Mol Cell 2010; 39: 152–160. and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 2010; 149 Munro S, Khaire N, Inche A, Carr S, La Thangue NB. Lysine methylation regulates 285: 9636–9641. the pRb tumour suppressor protein. Oncogene 2010; 29: 2357–2367. 169 Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD et al. ncRNA- and Pc2 150 Carr SM, Munro S, Kessler B, Oppermann U, La Thangue NB. Interplay between methylation-dependent gene relocation between nuclear structures mediates lysine methylation and Cdk phosphorylation in growth control by the retino- gene activation programs. Cell 2011; 147: 773–788. blastoma protein. EMBO J 2011; 30: 317–327. 170 Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY et al. EZH2 generates a methyl 151 Subramanian K, Jia D, Kapoor-Vazirani P, Powell DR, Collins RE, Sharma D et al. degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase Regulation of by the SET7 lysine methyltransferase. Mol complex. Mol Cell 2012; 48: 572–586. Cell 2008; 30: 336–347. 171 Kachirskaia I, Shi X, Yamaguchi H, Tanoue K, Wen H, Wang EW et al. Role for 152 Gaughan L, Stockley J, Wang N, McCracken SR, Treumann A, Armstrong K et al. 53BP1 Tudor domain recognition of p53 dimethylated at lysine 382 in DNA Regulation of the androgen receptor by SET9-mediated methylation. Nucleic damage signaling. J Biol Chem 2008; 283: 34660–34666. Acids Res 2011; 39: 1266–1279. 172 Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M et al. p53 is 153 Ko S, Ahn J, Song CS, Kim S, Knapczyk-Stwora K, Chatterjee B. Lysine methylation regulated by the lysine demethylase LSD1. Nature 2007; 449: 105–108. and functional modulation of androgen receptor by Set9 methyltransferase. Mol 173 Krajewski WA, Reese JC. SET domains of histone methyltransferases recognize Endocrinol 2011; 25: 433–444. ISWI-remodeled nucleosomal species. Mol Cell Biol 2009; 30: 552–564.

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