HMTs Suv39h1 (K9 H3) RIZ1 (K9 H3) Suv4-20h (K20 H4) SET8 (K20 H4) MBDs MeCP2 MBD1 MBD2 MBD3 Repressors PcG BMI1 EZH2 HDACs HDAC1 HDAC2 DNMTs DNMT1 DNMT3b Gene DNMT1 DNMT3b MeCP2 MBD2 MBD1 MBD3 MBD4 p300 CBP pCAF MOZ MORF MOF HDAC1 HDAC2 SIRT1 SUV39H1 Suv4-20h PR/SET7,8 RIZ1 MLL1 BMI1 EZH2 EMSY BRMS1 MTA1 MTA3 PASG/LSH BRG1 HLTF SNF5 Function DNA methyltransferase DNA methyltransferase Methyl-CpG-binding protein Methyl-CpG-binding protein Methyl-CpG-binding protein Methyl-CpG-binding protein Methyl-CpG-binding protein Histone acetyltransferase Histone acetyltransferase Histone acetyltransferase Histone acetyltransferase Histone acetyltransferase Histone acetyltransferase Histone deacetylase Histone deacetylase Histone deacetylase Histone methyltransferase Histone methyltransferase Histone methyltransferase Histone methyltransferase Histone methyltransferase Polycomb-group protein Polycomb-group protein Chromatin-remodelling factor Chromatin-remodelling factor Chromatin-remodelling factor Chromatin-remodelling factor SWI/SNF family protein SWI/SNF family protein SWI/SNF family protein SWI/SNF family protein MSI+ ¼ microsatellite instable tumours. British Journal of Cancer (2006) 94(2), 179 – 183 Epigenetics M Esteller 180 genes? Could these genes be targeted with new drugs? Let us review the data that is summarised in Figure 1 and Table 1. GENES MEDIATING THE DISRUPTION OF DNA METHYLATION It has been known for a long time that there is more enzymatic DNA methyltransferase activity overall in tumours than in normal tissues (Esteller, 2005a, b). This finding has been supported by the molecular characterisation of the genes encoding several DNA methyltranferases (DNMT1, DNMT3a, DNMT3b, DNMT3L and DNMT2), which has shown that the number of mRNA transcripts of DNMT1 (the classical methylation maintenance enzyme) and DNMT3b (the de novo methylation enzyme) are greater in several solid and haematological malig- nancies (Esteller, 2005a). CH3CH3CH3 CH3 CH3 CH3CH3 CH3 Tumour–suppressor gene Oncogene Figure 1 Epigenetic proteins that contribute to human tumorigenesis. Silencing of a classical tumours suppressor gene involves the recruitment of a transcriptional repressor machinery to the corresponding promoter CpG island, such as DNA methyltransferases (DNMT), methyl-CpG-binding proteins (MBD), histone methyltransferases for lysine 9 of histone H3 (HMT K9 H3), histone deacetylases (HDAC) and polycomb (PcGs) complexes. In the other side of the coin, the active expression of oncogenes in human cancer requires a potent transcriptional activation machinery, such as the one constituted by the chromatin-remodelling factors SWI/SNF, histone acetyltransferases (HATs) and histone methyltransferases for lysine 4 of histone H3 (HMT K4 H3). Table 1 A selected list of epigenetic genes disrupted in human cancer and additional potential candidates HATs p300 CBP pCAF MOZ MORF MOF HMTs MLL1 (K4 H3) Activators SWI/SNF PASG/LSH BRG1 HLTF SNF5 Alteration Overexpression Overexpression Overexpression, rare mutations Overexpression, rare mutations Overexpression, rare mutations Overexpression, rare mutations Inactivating mutations in MSI+ Mutations Mutations, homozygous deletions Rare mutations Translocations Translocations Unknown Imbalanced expression Imbalanced expression Unknown Unknown Unknown Unknown CpG island hypermethylation, mutation Translocation Gene amplification, overexpression Gene amplification, overexpression Gene amplification, overexpression Loss of expression Overexpression Overexpression Mutation Homozygous deletion, mutation CpG island hypermethylation Somatic and germline mutations Tumour profile Multiple types Multiple types Multiple types Multiple types Multiple types Multiple types Colon, stomach, endometrium Colon, stomach, endometrium Colon, stomach, endometrium, lung Colon Haematological malignancies Haematological malignancies Unknown Multiple types Multiple types Unknown Unknown Unknown Unknown Multiple types Haematological malignancies Haematological malignancies, brain Multiple types Breast Breast Breast, haematological malignancies Breast, haematological malignancies Haematological malignancies Lung Multiple types Rhabdoid tumours & 2006 Cancer Research UK