Targeting the Epigenome for Treatment of Cancer
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Oncogene (2012) 31, 3827–3844 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc REVIEW Targeting the epigenome for treatment of cancer E-J Geutjes, PK Bajpe and R Bernards Division of Molecular Carcinogenesis, Centre for Biomedical Genetics and Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands Cancer genome analyses have revealed that the enzymes required for normal cellular physiology. Moreover, involved in epigenetic gene regulation are frequently epimutations can outnumber genetic abnormalities and deregulated in cancer. Here we describe the enzymes that often occur early in cancer development (Esteller et al., control the epigenetic state of the cell, how they are 1999; Schuebel et al., 2007; Chen et al., 2009). Such affected in cancer and how this knowledge can be epimutated genes are often tumour-suppressor genes exploited to treat cancer with a new arsenal of selective (TSGs), including the DNA-repair proteins MutL therapies. homologue-1 (MLH1)andBRCA1, the INK4A-ARF Oncogene (2012) 31, 3827–3844; doi:10.1038/onc.2011.552; locus-encoded cell-cycle inhibitors (CDKN2A and published online 5 December 2011 CDKN2B) and von Hippel–Lindau (VHL), which controls cell survival and angiogenesis. Many epigenetic Keywords: cancer epigenetics; epigenetic therapy; DNA regulators, including those responsible for silencing of methylation; histone modifications; nucleosome the above mentioned TSGs, are deregulated in cancer. remodelling Recent cancer genome analyses have identified an impressive and still increasing number of epigenetic enzymes that are deregulated in many types of cancers, establishing a direct link between cancer genetics and Introduction cancer epigenetics. Recurrent loss-of-function and gain- of-function mutations affecting nucleosome-remodelling Epigenetics is the study of heritable changes in gene complexes, histone modifiers and DNA-modifying en- expression that do not involve alterations of the DNA zymes occur in many cancers (Table 1 and discussed sequence (Kelly et al., 2010). Many of these changes below), clearly demonstrating that at least three major involve alterations of the chromatin: the state in which epigenetic mechanisms are deregulated in cancer. DNA is stored inside the cell. Eukaryotic DNA is Epigenetic enzymes are attractive drug targets because packaged in nucleosomes, which comprise octamers of of the reversible nature of epigenetic modifications. The four core histone proteins (H2A, H2B, H3 and H4) recognition that epigenetic enzymes are frequently around which 147 bp of DNA is wrapped. Accessibility deregulated in cancer has fuelled the development of of DNA is determined by repositioning and restructur- inhibitors of these, referred to here as ‘epigenetic drugs’. ing of the nucleosomes by ATP-dependent chromatin Epigenetic drugs can be divided into two classes. The remodellers, through covalent modifications of the first class consists of non-selective agents, including the histones by histone-modifying enzymes and through clinically used inhibitors of DNA methyltransferases modifications on the DNA itself by DNA-modifying (DNMTi) and histone deacetylases (HDACi), and the enzymes. There is substantial interplay between the more recently discovered inhibitors of EZH2 and LSD1. many epigenetic regulators, which together control Of this class, both DNMTis and HDACis are approved transcription. Globally, chromatin can be in two states, for treatment of cancer. The second class consists of the open state (euchromatin) in which DNA is available more selective inhibitors, including those targeting for transcription and a closed state (heterochromatin) JAK2, G9a/GLP and DOT1L. In this review, we will in which the DNA is tightly packed, precluding its discuss those epigenetic enzymes deregulated in cancer transcription. and the feasibility to target these for cancer therapy. In addition to alterations in the primary DNA sequence, cancers often harbour multiple epigenetic DNA-modifying enzymes alterations, here referred to as epimutations, which also DNMTs convert the cytosine residues of CpG dinucleo- affect key regulatory signalling pathways that are tides into 5-methylcytosine, which can be further converted into 5-hydroxymethyl-20-deoxycytidine by Correspondence: Dr R Bernards, Division of Molecular Carcinogen- the Ten-Eleven-Translocation (TET) family (Tahiliani esis, Centre for Biomedical Genetics and Cancer Genomics Centre, et al., 2009; Ito et al., 2010). CpG dinucleotides are The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, highly enriched in small genomic regions, known as Amsterdam, The Netherlands. E-mail: [email protected] CpG islands, which frequently coincide with promoter Received 1 October 2011; accepted 27 October 2011; published online 5 regions. Most CpG dinucleotides are methylated except December 2011 those found in the promoter-located CpG islands, Targeting the epigenome for cancer treatment E-J Geutjes et al 3828 Table 1 Selection of epigenetic enzymes deregulated in cancer Epigenetic Function Cancer type Alteration Reference regulator DNA-modifying enzymes DNMT3A Converts cytosine residues AML, MDS Mutations (Ley et al., 2010; Yan et al., 2011) to 5-methylcytosine TET2 Converts methylcytosine AML, MDS, MF Deletions, missense (Delhommeau et al., 2009; to hydroxy methylcytosine and nonsense Langemeijer et al., 2009; mutations Ko et al., 2010) Histone-modifying enzymes Lysine acetyltransferases p300/CBP Acetylates histones H3, MDS, B-cell non- Translocations, (Lavau et al., 2000; Gui et al., 2011; H4 and non-histone proteins Hodgkin’s lymphoma mutations Mullighan et al., 2011; and bladder cancer Pasqualucci et al., 2011) TIP60 Histones H2A and H4 Breast carcinoma LOH Gorrini et al. (2007) MYST3 Histones H2A and H4 Leukaemia, Translocations, (Kitabayashi et al., 2001b; medulloblastoma amplification Northcott et al., 2009) AIB-1 Co-activator Breast cancer, Amplification (Anzick et al., 1997; Sakakura et al., oesophageal cancer, 2000; Miller et al., 2003) gastric cancer TRRAP Adaptor protein for HAT Melanoma Mutations Wei et al. (2008b) (2011) complexes Lysine deacetylases HDAC1 Deacetylates histones and Prostate, gastric, colon Overexpression (Choi et al., 2001; Halkidou et al., non-histone proteins and breast cancers 2004; Zhang et al., 2005; Wilson et al., 2006; Weichert et al., 2008a) HDAC2 Deacetylates histones and Colorectal, cervical and Overexpression (Song et al., 2005; Weichert et al., non-histone proteins gastric cancers 2008a, 2008b) HDAC3 Deacetylates non-histone Ovarian cancer Overexpression Jin et al. (2008) proteins HDAC6 Deacetylates non-histone Breast cancer Overexpression Saji et al. (2005) proteins HDAC8 Deacetylates histones Neuroblastoma Overexpression Oehme et al. (2009) Lysine methyltransferases G9a/KMT1C Histone H3K9 mono- and Lung and hepatocellular Overexpression (Kondo et al., 2008; Chen et al., 2010) dimethylase carcinoma SETDB1 Histone H3K9 trimethylase Melanoma Amplification Ceol et al. (2011) MLL1 Histone H3H4 trimethylase ALL, AML Translocations (Liu et al., 2009b; Marschalek, 2011) MLL2 and Histone H3H4 trimethylase Non-Hodgkin’s lym- Inactivating (Dalgliesh et al., 2010; Morin et al., MLL3 phoma, renal carcinoma mutations 2011; Parsons et al., 2011) and medulloblastoma EZH2 Histone H3K27 trimethylase Prostate, breast, endo- Amplification, (Varambally et al., 2002; Kleer et al., metrium, B-cell non- overexpression, 2003; Arisan et al., 2005; Raman et al., Hodgkin’s lymphoma gain-of-function 2005; Sudo et al., 2005; Weikert et al., and bladder carcinoma mutation 2005; Matsukawa et al., 2006) SETD2 Histone H3K36 methylase Clear cell renal Truncating mutations, (Dalgliesh et al., 2010; Varela et al., carcinoma, AML translocations 2011) NSD1 Histone H3K36 methylase Sotos syndrome, AML, Translocations, (Jaju et al., 2001; Kurotaki et al., 2002; neuroblastoma, glioma mutations, promoter Berdasco et al., 2009) methylation KMT8/RIZ1 Histone H3K9 trimethylase Colorectal cancer, Missense, frame shift (He et al., 1998; Chadwick et al., 2000; DLBL mutations, promoter Steele-Perkins et al., 2001) methylation Lysine demethylases KDM1A Histone H3K4me1/2 and Prostate and breast Overexpression (Metzger et al., 2005; Kahl et al., 2006; H3K9me1/2 demethylase cancer and neuroblastoma Schulte et al., 2009; Lim et al., 2010) KDM2B Histone H3K4 and K36 Lymphomas and Overexpression Frescas et al. (2008) demethylase adenocarcinomas KDM4C H3K9 and H3K36 Prostate cancer, breast Amplification, (Yang et al., 2000; Ehrbrecht et al., demethylase cancer, lymphoma, overexpression 2006; Liu et al., 2009a; Rui et al., 2010) medulloblastoma, oesophageal cancer KDM5A Histone H3K4 demethylase AML Translocations (Wang et al., 2009a; Zeng et al., 2010) KDM5B Histone H3K4 demethylase Breast and prostate Overexpression, (Lu et al., 1999; Roesch et al., 2005; cancer, melanoma downregulation Xiang et al., 2007) KDM5C Histone H3K4 demethylase Renal cell carcinoma Inactivating mutations (Dalgliesh et al., 2010; Varela et al., 2011) KDM6A Histone H3K27 demethylase Lymphoma, renal cell Inactivating mutations (van Haaften et al., 2009; Dalgliesh carcinoma and bladder et al., 2010; Gui et al., 2011; Varela carcinoma et al., 2011; Wartman et al., 2011) Oncogene Targeting the epigenome for cancer treatment E-J Geutjes et al 3829 Table 1 Continued Epigenetic Function Cancer type Alteration Reference regulator Ubiquitin ligases BMI1 Cooperates with Ring1B B-cell lymphoma Amplification and (Bea et al., 2001; Rubio-Moscardo