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Selective Inhibition of Acetyl-Lysine Effector Domains of the Bromodomain Family in Oncology

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Nuclear Signaling Pathways and Targeting Transcription in Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Acetylation of lysine residues is a posttranslational modification that plays a key role in the regulation of chromatin structure and transcription. In cancer, aberrant lysine acetylation often leads to changes in gene expression resulting in inactivation of tumour suppressor functions and the activation of pro-survival and proliferation promoting pathways. Enzymes that “write” (acetyltransferases, HATs) and “erase” (histone deacetylases, HDACs) ε-N-acetyl-lysine (Kac) marks have therefore emerged as interesting targets for the development of novel drugs for cancer treatment. Recently also acetyl-lysine reader domains have gained interest as novel targets for pharmacological intervention. The acetyl-lysine mark is specifically recognized by the bromodomain family of protein interaction modules. Bromodomains are present in diverse nuclear proteins regulating the recruitment of transcriptional regulators and chromatin modifying enzymes and proteins to acetylated chromatin as well as proteins mediating the assembly of other nuclear protein complexes. Dysfunction of bromodomain containing proteins such as chromosomal rearrangements and aberrant expression of these proteins in cancer has been tightly linked to tumourigenesis. Recently identified inhibitors that selectively target bromodomains demonstrated potent anti-tumour activity, suggesting new avenues for the development of antineoplastic drugs. In this chapter we will review the current knowledge of the role of bromodomains in tumour development and identified selective inhibitors developed to disrupt acetyl-lysine dependent protein interactions mediated by this family of transcriptional regulators.

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Abbreviations

AML:

Acute myeloid leukemia

ASH1L:

Absent, small or homeotic-like

ATAD2A/B:

AAA domain-containing protein 2

ATP:

Adenosine triphosphate

BAZ:

Bromodomain adjacent to zinc finger domain protein

BCL2:

B-cell lymphoma 2

BET:

Bromodomain and extra-terminal

BRD:

Bromodomain-containing

BRPF:

Bromodomain and PHD finger-containing protein

BRWD:

Bromodomain and WD repeat-containing protein

CECR:

Cat eye syndrome critical region

CML:

Chronic myeloid leukemia

c-MYC:

V-myc myelocytomatosis viral oncogene homolog

CREBBP:

CREB-binding protein

EP300:

Histone acetyltransferase p300

FALZ:

Fetal Alzheimer antigene

FOSL1:

FOS-like antigen 1

GCN5L2:

General control of amino acid synthesis protein 5-like 2

HAT:

Histone acetyltransferase

HBO1:

HAT bound to Orc1

HCF-1:

Host cell factor 1

HDAC:

Histone deacetylase

HIV:

Human immunodeficiency virus

hMOF:

Human ortholog of fly mof, MOF, for males absent on the first

MLL:

Mixed Linage Leukemia

MORF:

MOZ-related factor

MOZ:

Monocytic leukemic zinc finger protein

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NMC:

NUT midline carcinoma

NSCLC:

Non-small cell lung cancer

NUT:

Nuclear protein in testis

PB1:

Polybromo 1, PBAF, Polybromo and Brg1-associated factor

PCAF:

P300/CBP associated factor

PHIP:

PH-interacting protein

PRKCBP1:

Protein kinase C-binding protein 1

P-TEFb:

Positive transcription elongation factor complex (cdk9/cyclinT)

Rara:

Retinoic acid receptor alpha

RNA:

Ribonucleic acid

siRNA:

Small interfering RNA/Short interfering RNA

SIRT:

Sirtuin

SMARCA:

SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin

SP100/110/140:

Nuclear body protein

SWI/SNF:

SWItch/Sucrose NonFermentable

TAF1/TAF1L:

Transcription initiation TFIID associated factor

Tat:

Trans-activator of transcription

TIP60:

HIV Tat-interactive protein of 60 kDa

TRIM24/28/33/66:

Transcription intermediary factor 1-alpha (TIF1α)

WDR9:

Bromodomain and WD repeat-containing protein 1

ZMYND11:

Zinc finger MYND domain-containing protein 11

References

  1. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840, Epub 2009/07/18

    PubMed  CAS  Google Scholar 

  2. Barneda-Zahonero B, Parra M (2012) Histone deacetylases and cancer. Mol Oncol 6(6):579–589, Epub 2012/09/12

    PubMed  CAS  Google Scholar 

  3. Parra M, Verdin E (2010) Regulatory signal transduction pathways for class IIa histone deacetylases. Curr Opin Pharmacol 10(4):454–460, Epub 2010/05/08

    PubMed  CAS  Google Scholar 

  4. Ropero S, Fraga MF, Ballestar E, Hamelin R, Yamamoto H, Boix-Chornet M et al (2006) A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat Genet 38(5):566–569, Epub 2006/04/28

    PubMed  CAS  Google Scholar 

  5. Lee JH, Choy ML, Marks PA (2012) Mechanisms of resistance to histone deacetylase inhibitors. Adv Cancer Res 116:39–86, Epub 2012/10/24

    PubMed  CAS  Google Scholar 

  6. Hagelkruys A, Sawicka A, Rennmayr M, Seiser C (2011) The biology of HDAC in cancer: the nuclear and epigenetic components. Handb Exp Pharmacol 206:13–37, Epub 2011/09/01

    PubMed  CAS  Google Scholar 

  7. Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP et al (1998) Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391(6667):601–605, Epub 1998/02/19

    PubMed  CAS  Google Scholar 

  8. Buurman R, Gurlevik E, Schaffer V, Eilers M, Sandbothe M, Kreipe H et al (2012) Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 143(3):811–820, e1–15. Epub 2012/05/30

    PubMed  CAS  Google Scholar 

  9. Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90(1):85–94, Epub 2011/11/30

    PubMed  CAS  Google Scholar 

  10. Licciardi PV, Ververis K, Tang ML, El-Osta A, Karagiannis TC (2012) Immunomodulatory effects of histone deacetylase inhibitors. Curr Mol Med 13(4):640–647, Epub 2012/10/16

    Google Scholar 

  11. Marmorstein R, Trievel RC (2009) Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta 1789(1):58–68, Epub 2008/08/30

    PubMed  CAS  Google Scholar 

  12. Yang X, Yu W, Shi L, Sun L, Liang J, Yi X et al (2011) HAT4, a Golgi apparatus-anchored B-type histone acetyltransferase, acetylates free histone H4 and facilitates chromatin assembly. Mol Cell 44(1):39–50, Epub 2011/10/11

    PubMed  CAS  Google Scholar 

  13. Avvakumov N, Cote J (2007) The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene 26(37):5395–5407, Epub 2007/08/19

    PubMed  CAS  Google Scholar 

  14. Kouzarides T (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19(6):1176–1179, Epub 2000/03/16

    PubMed  CAS  Google Scholar 

  15. Tohyama S, Tomura A, Ikeda N, Hatano M, Odanaka J, Kubota Y et al (2012) Discovery and characterization of NK13650s, naturally occurring p300-selective histone acetyltransferase inhibitors. J Org Chem 77(20):9044–9052, Epub 2012/09/19

    PubMed  CAS  Google Scholar 

  16. Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D et al (2012) Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149(1):214–231, Epub 2012/04/03

    PubMed  CAS  Google Scholar 

  17. Haynes SR, Dollard C, Winston F, Beck S, Trowsdale J, Dawid IB (1992) The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Res 20(10):2603, Epub 1992/05/25

    PubMed  CAS  Google Scholar 

  18. Muller S, Filippakopoulos P, Knapp S (2011) Bromodomains as therapeutic targets. Expert Rev Mol Med 13:e29, Epub 2011/09/22

    PubMed  Google Scholar 

  19. Liu J, Lee W, Jiang Z, Chen Z, Jhunjhunwala S, Haverty PM et al (2012) Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res 22(12):2315–2327, Epub 2012/10/04

    PubMed  CAS  Google Scholar 

  20. Kalashnikova EV, Revenko AS, Gemo AT, Andrews NP, Tepper CG, Zou JX et al (2010) ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. Cancer Res 70(22):9402–9412, Epub 2010/09/25

    PubMed  CAS  Google Scholar 

  21. Zou JX, Revenko AS, Li LB, Gemo AT, Chen HW (2007) ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci USA 104(46):18067–18072, Epub 2007/11/14

    PubMed  CAS  Google Scholar 

  22. Duan Z, Zou JX, Yang P, Wang Y, Borowsky AD, Gao AC et al (2012) Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex. Prostate 73(5):455–466, Epub 2012/10/06

    PubMed  Google Scholar 

  23. Fouret R, Laffaire J, Hofman P, Beau-Faller M, Mazieres J, Validire P et al (2012) A comparative and integrative approach identifies ATPase family, AAA domain containing 2 as a likely driver of cell proliferation in lung adenocarcinoma. Clin Cancer Res 18(20):5606–5616, Epub 2012/08/24

    PubMed  CAS  Google Scholar 

  24. Leachman NT, Brellier F, Ferralli J, Chiquet-Ehrismann R, Tucker RP (2010) ATAD2B is a phylogenetically conserved nuclear protein expressed during neuronal differentiation and tumorigenesis. Dev Growth Differ 52(9):747–755, Epub 2010/12/17

    PubMed  CAS  Google Scholar 

  25. Revenko AS, Kalashnikova EV, Gemo AT, Zou JX, Chen HW (2010) Chromatin loading of E2F-MLL complex by cancer-associated coregulator ANCCA via reading a specific histone mark. Mol Cell Biol 30(22):5260–5272, Epub 2010/09/22

    PubMed  CAS  Google Scholar 

  26. Hennig EE, Mikula M, Rubel T, Dadlez M, Ostrowski J (2012) Comparative kinome analysis to identify putative colon tumor biomarkers. J Mol Med (Berl) 90(4):447–456, Epub 2011/11/19

    CAS  Google Scholar 

  27. Panagopoulos I, Strombeck B, Isaksson M, Heldrup J, Olofsson T, Johansson B (2006) Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement. Br J Haematol 133(3):270–275, Epub 2006/04/29

    PubMed  CAS  Google Scholar 

  28. Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas OA et al (2009) Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia 23(1):134–143, Epub 2008/11/21

    PubMed  CAS  Google Scholar 

  29. Viejo-Borbolla A, Ottinger M, Bruning E, Burger A, Konig R, Kati E et al (2005) Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi’s Sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J Virol 79(21):13618–13629, Epub 2005/10/18

    PubMed  CAS  Google Scholar 

  30. Zhou M, Peng C, Nie XM, Zhang BC, Zhu SG, Yu Y et al (2003) Expression of BRD7-interacting proteins, BRD2 and BRD3, in nasopharyngeal carcinoma tissues. Chin J Cancer 22(2):123–127

    CAS  Google Scholar 

  31. French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, Thyne ME et al (2008) BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27(15):2237–2242, Epub 2007/10/16

    PubMed  CAS  Google Scholar 

  32. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI et al (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478(7370):529–533, Epub 2011/10/04

    PubMed  CAS  Google Scholar 

  33. French CA (2012) Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 7:247–265, Epub 2011/10/25

    PubMed  CAS  Google Scholar 

  34. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM et al (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146(6):904–917, Epub 2011/09/06

    PubMed  CAS  Google Scholar 

  35. Lockwood WW, Zejnullahu K, Bradner JE, Varmus H (2012) Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA 109(47):19408–19413, Epub 2012/11/07

    PubMed  CAS  Google Scholar 

  36. You J, Srinivasan V, Denis GV, Harrington WJ Jr, Ballestas ME, Kaye KM et al (2006) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 80(18):8909–8919, Epub 2006/08/31

    PubMed  CAS  Google Scholar 

  37. Grunwald C, Koslowski M, Arsiray T, Dhaene K, Praet M, Victor A et al (2006) Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer. Int J Cancer 118(10):2522–2528, Epub 2005/12/15

    PubMed  CAS  Google Scholar 

  38. Drost J, Mantovani F, Tocco F, Elkon R, Comel A, Holstege H et al (2010) BRD7 is a candidate tumour suppressor gene required for p53 function. Nat Cell Biol 12(4):380–389, Epub 2010/03/17

    PubMed  CAS  Google Scholar 

  39. Yamada HY, Rao CV (2009) BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy. Int J Oncol 35(5):1101–1109, Epub 2009/09/30

    PubMed  CAS  Google Scholar 

  40. Kang JU, Koo SH, Kwon KC, Park JW, Kim JM (2008) Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non-small cell lung cancer. Cancer Genet Cytogenet 182(1):1–11, Epub 2008/03/11

    PubMed  CAS  Google Scholar 

  41. Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB et al (2008) The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development 135(11):1935–1946, Epub 2008/05/13

    PubMed  CAS  Google Scholar 

  42. Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C et al (2008) Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol 28(22):6828–6843, Epub 2008/09/17

    PubMed  CAS  Google Scholar 

  43. Kalla C, Nentwich H, Schlotter M, Mertens D, Wildenberger K, Dohner H et al (2005) Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes. Genes Chromosomes Cancer 42(2):128–143, Epub 2004/11/16

    PubMed  CAS  Google Scholar 

  44. Lee SK, Park EJ, Lee HS, Lee YS, Kwon J (2012) Genome-wide screen of human bromodomain-containing proteins identifies Cecr2 as a novel DNA damage response protein. Mol Cells 34(1):85–91, Epub 2012/06/16

    PubMed  CAS  Google Scholar 

  45. Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA et al (2011) CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471(7337):235–239, Epub 2011/03/11

    PubMed  CAS  Google Scholar 

  46. Gong AY, Eischeid AN, Xiao J, Zhao J, Chen D, Wang ZY et al (2012) miR-17-5p targets the p300/CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells. BMC Cancer 12(1):492, Epub 2012/10/26

    PubMed  CAS  Google Scholar 

  47. Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF et al (2000) Mutations truncating the EP300 acetylase in human cancers. Nat Genet 24(3):300–303, Epub 2000/03/04

    PubMed  CAS  Google Scholar 

  48. Chaffanet M, Gressin L, Preudhomme C, Soenen-Cornu V, Birnbaum D, Pebusque MJ (2000) MOZ is fused to p300 in an acute monocytic leukemia with t(8;22). Genes Chromosomes Cancer 28(2):138–144, Epub 2000/05/29

    PubMed  CAS  Google Scholar 

  49. Grinberg-Rashi H, Ofek E, Perelman M, Skarda J, Yaron P, Hajduch M et al (2009) The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res 15(5):1755–1761, Epub 2009/02/05

    PubMed  CAS  Google Scholar 

  50. Krivtsov AV, Armstrong SA (2007) MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7(11):823–833, Epub 2007/10/25

    PubMed  CAS  Google Scholar 

  51. Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P et al (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469(7331):539–542, Epub 2011/01/21

    PubMed  CAS  Google Scholar 

  52. Xia W, Nagase S, Montia AG, Kalachikov SM, Keniry M, Su T et al (2008) BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer. Cancer Res 68(6):1667–1674, Epub 2008/03/15

    PubMed  CAS  Google Scholar 

  53. Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y (1996) A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382(6589):319–324, Epub 1996/07/25

    PubMed  CAS  Google Scholar 

  54. Ge X, Jin Q, Zhang F, Yan T, Zhai Q (2009) PCAF acetylates {beta}-catenin and improves its stability. Mol Biol Cell 20(1):419–427, Epub 2008/11/07

    PubMed  CAS  Google Scholar 

  55. Armas-Pineda C, Arenas-Huertero F, Perezpenia-Diazconti M, Chico-Ponce de Leon F, Sosa-Sainz G, Lezama P et al (2007) Expression of PCAF, p300 and Gcn5 and more highly acetylated histone H4 in pediatric tumors. J Exp Clin Cancer Res 26(2):269–276, Epub 2007/08/30

    PubMed  CAS  Google Scholar 

  56. De Semir D, Nosrati M, Bezrookove V, Dar AA, Federman S, Bienvenu G et al (2012) Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Proc Natl Acad Sci USA 109(18):7067–7072, Epub 2012/04/19

    PubMed  Google Scholar 

  57. Tokuda E, Fujita N, Oh-hara T, Sato S, Kurata A, Katayama R et al (2007) Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo. Cancer Res 67(20):9666–9676, Epub 2007/10/19

    PubMed  CAS  Google Scholar 

  58. Eichmuller S, Usener D, Dummer R, Stein A, Thiel D, Schadendorf D (2001) Serological detection of cutaneous T-cell lymphoma-associated antigens. Proc Natl Acad Sci USA 98(2):629–634, Epub 2001/01/10

    PubMed  CAS  Google Scholar 

  59. Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M et al (2012) Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc Natl Acad Sci USA 109(5):E252–E259, Epub 2012/01/12

    PubMed  CAS  Google Scholar 

  60. Liu G, Gramling S, Munoz D, Cheng D, Azad AK, Mirshams M et al (2011) Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk. Oncogene 30(29):3295–3304, Epub 2011/04/12

    PubMed  CAS  Google Scholar 

  61. Reisman D, Glaros S, Thompson EA (2009) The SWI/SNF complex and cancer. Oncogene 28(14):1653–1668, Epub 2009/02/24

    PubMed  CAS  Google Scholar 

  62. Schneppenheim R, Fruhwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U et al (2010) Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86(2):279–284, Epub 2010/02/09

    PubMed  CAS  Google Scholar 

  63. Negorev DG, Vladimirova OV, Kossenkov AV, Nikonova EV, Demarest RM, Capobianco AJ et al (2010) Sp100 as a potent tumor suppressor: accelerated senescence and rapid malignant transformation of human fibroblasts through modulation of an embryonic stem cell program. Cancer Res 70(23):9991–10001, Epub 2010/12/02

    PubMed  CAS  Google Scholar 

  64. Yordy JS, Moussa O, Pei H, Chaussabel D, Li R, Watson DK (2005) SP100 inhibits ETS1 activity in primary endothelial cells. Oncogene 24(5):916–931, Epub 2004/12/14

    PubMed  CAS  Google Scholar 

  65. Nicewonger J, Suck G, Bloch D, Swaminathan S (2004) Epstein-Barr virus (EBV) SM protein induces and recruits cellular Sp110b to stabilize mRNAs and enhance EBV lytic gene expression. J Virol 78(17):9412–9422, Epub 2004/08/17

    PubMed  CAS  Google Scholar 

  66. Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R et al (2008) A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet 40(10):1204–1210, Epub 2008/09/02

    PubMed  Google Scholar 

  67. Chambon M, Orsetti B, Berthe ML, Bascoul-Mollevi C, Rodriguez C, Duong V et al (2011) Prognostic significance of TRIM24/TIF-1alpha gene expression in breast cancer. Am J Pathol 178(4):1461–1469, Epub 2011/03/26

    PubMed  CAS  Google Scholar 

  68. Li H, Sun L, Tang Z, Fu L, Xu Y, Li Z et al (2012) Overexpression of TRIM24 correlates with tumor progression in non-small cell lung cancer. PLoS One 7(5):e37657, Epub 2012/06/06

    PubMed  CAS  Google Scholar 

  69. Herquel B, Ouararhni K, Khetchoumian K, Ignat M, Teletin M, Mark M et al (2011) Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma. Proc Natl Acad Sci USA 108(20):8212–8217, Epub 2011/05/03

    PubMed  CAS  Google Scholar 

  70. Khetchoumian K, Teletin M, Tisserand J, Mark M, Herquel B, Ignat M et al (2007) Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha. Nat Genet 39(12):1500–1506, Epub 2007/11/21

    PubMed  CAS  Google Scholar 

  71. Tsai WW, Wang Z, Yiu TT, Akdemir KC, Xia W, Winter S et al (2010) TRIM24 links a non-canonical histone signature to breast cancer. Nature 468(7326):927–932, Epub 2010/12/18

    PubMed  CAS  Google Scholar 

  72. Yang H, Zhang C, Zhao X, Wu Q, Fu X, Yu B et al (2010) Analysis of copy number variations of BS69 in multiple types of hematological malignancies. Ann Hematol 89(10):959–964, Epub 2010/04/29

    PubMed  CAS  Google Scholar 

  73. Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF et al (2003) EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115(5):523–535, Epub 2003/12/04

    PubMed  CAS  Google Scholar 

  74. Moriniere J, Rousseaux S, Steuerwald U, Soler-Lopez M, Curtet S, Vitte AL et al (2009) Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461(7264):664–668

    PubMed  CAS  Google Scholar 

  75. Vidler LR, Brown N, Knapp S, Hoelder S (2012) Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites. J Med Chem 55(17):7346–7359, Epub 2012/07/14

    PubMed  CAS  Google Scholar 

  76. Zeng L, Li J, Muller M, Yan S, Mujtaba S, Pan C et al (2005) Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J Am Chem Soc 127(8):2376–2377, Epub 2005/02/24

    PubMed  CAS  Google Scholar 

  77. Sachchidanand, Resnick-Silverman L, Yan S, Mutjaba S, Liu WJ, Zeng L et al (2006) Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. Chem Biol 13(1):81–90, Epub 2006/01/24

    PubMed  CAS  Google Scholar 

  78. Borah JC, Mujtaba S, Karakikes I, Zeng L, Muller M, Patel J et al (2011) A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem Biol 18(4):531–541, Epub 2011/04/26

    PubMed  CAS  Google Scholar 

  79. Demont E, Gosmini R (2011) Tetrahydroquinoline derivatives as bromodomain inhibitors. International patent WO/2011/054848. GLAXOSMITHKLINE LLC:1–199

    Google Scholar 

  80. Ito T, Umehara T, Sasaki K, Nakamura Y, Nishino N, Terada T et al (2011) Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem Biol 18(4):495–507, Epub 2011/04/26

    PubMed  CAS  Google Scholar 

  81. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O et al (2010) Selective inhibition of BET bromodomains. Nature 468(7327):1067–1073, Epub 2010/09/28

    PubMed  CAS  Google Scholar 

  82. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW et al (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468(7327):1119–1123, Epub 2010/11/12

    PubMed  CAS  Google Scholar 

  83. Chung CW, Coste H, White JH, Mirguet O, Wilde J, Gosmini RL et al (2011) Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem 54(11):3827–3838, Epub 2011/05/17

    PubMed  CAS  Google Scholar 

  84. Filippakopoulos P, Picaud S, Fedorov O, Keller M, Wrobel M, Morgenstern O et al (2012) Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg Med Chem 20(6):1878–1886, Epub 2011/12/06

    PubMed  CAS  Google Scholar 

  85. Hewings DS, Wang M, Philpott M, Fedorov O, Uttarkar S, Filippakopoulos P et al (2011) 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J Med Chem 54(19):6761–6770, Epub 2011/08/20

    PubMed  CAS  Google Scholar 

  86. Bamborough P, Diallo H, Goodacre JD, Gordon L, Lewis A, Seal JT et al (2012) Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. J Med Chem 55(2):587–596, Epub 2011/12/06

    PubMed  CAS  Google Scholar 

  87. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA (2003) BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63(2):304–307, Epub 2003/01/25

    PubMed  CAS  Google Scholar 

  88. French CA (2010) Demystified molecular pathology of NUT midline carcinomas. J Clin Pathol 63(6):492–496, Epub 2008/06/17

    PubMed  Google Scholar 

  89. Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD et al (2000) Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J Natl Cancer Inst 92(16):1355–1357, Epub 2000/08/17

    PubMed  CAS  Google Scholar 

  90. Iyer NG, Ozdag H, Caldas C (2004) p300/CBP and cancer. Oncogene 23(24):4225–4231, Epub 2004/05/25

    PubMed  CAS  Google Scholar 

  91. Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS et al (1996) The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 14(1):33–41, Epub 1996/09/01

    PubMed  CAS  Google Scholar 

  92. Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U, Billstrom R, Strombeck B et al (2001) Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum Mol Genet 10(4):395–404, Epub 2001/02/07

    PubMed  CAS  Google Scholar 

  93. Lai JL, Jouet JP, Bauters F, Deminatti M (1985) Chronic myelogenous leukemia with translocation (8;22): report of a new case. Cancer Genet Cytogenet 17(4):365–366, Epub 1985/08/01

    PubMed  CAS  Google Scholar 

  94. Kitabayashi I, Aikawa Y, Yokoyama A, Hosoda F, Nagai M, Kakazu N et al (2001) Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. Leukemia 15(1):89–94, Epub 2001/03/13

    PubMed  CAS  Google Scholar 

  95. Rowley JD, Reshmi S, Sobulo O, Musvee T, Anastasi J, Raimondi S et al (1997) All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 90(2):535–541

    PubMed  CAS  Google Scholar 

  96. Satake N, Ishida Y, Otoh Y, Hinohara S, Kobayashi H, Sakashita A et al (1997) Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16)(q23;p13) chromosome translocation. Genes Chromosomes Cancer 20(1):60–63, Epub 1997/09/18

    PubMed  CAS  Google Scholar 

  97. Giles RH, Petrij F, Dauwerse HG, den Hollander AI, Lushnikova T, van Ommen GJ et al (1997) Construction of a 1.2-Mb contig surrounding, and molecular analysis of, the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3. Genomics 42(1):96–114

    PubMed  CAS  Google Scholar 

  98. Quintas-Cardama A, Qiu YH, Post SM, Zhang Y, Creighton CJ, Cortes J et al (2012) Reverse phase protein array profiling reveals distinct proteomic signatures associated with chronic myeloid leukemia progression and with chronic phase in the CD34-positive compartment. Cancer 118(21):5283–5292, Epub 2012/04/21

    PubMed  CAS  Google Scholar 

  99. Ding WM, Yang L, Zheng Y, Sun HY, Liang H, Wang JJ (2012) Preparation of anti-BRDT-NY polyclonal antibody and expression of BRDT-NY protein in digestive tract tumors. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 28(8):847–850, Epub 2012/08/07

    PubMed  CAS  Google Scholar 

  100. Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J et al (2002) Gene expression patterns in human liver cancers. Mol Biol Cell 13(6):1929–1939, Epub 2002/06/12

    PubMed  CAS  Google Scholar 

  101. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769):503–511, Epub 2000/02/17

    PubMed  CAS  Google Scholar 

  102. van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536, Epub 2002/02/02

    Google Scholar 

  103. Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuary P et al (2003) Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA 100(10):5974–5979, Epub 2003/04/26

    PubMed  CAS  Google Scholar 

  104. Caron C, Lestrat C, Marsal S, Escoffier E, Curtet S, Virolle V et al (2010) Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers. Oncogene 29(37):5171–5181, Epub 2010/06/29

    PubMed  CAS  Google Scholar 

  105. Ciro M, Prosperini E, Quarto M, Grazini U, Walfridsson J, McBlane F et al (2009) ATAD2 is a novel cofactor for MYC, overexpressed and amplified in aggressive tumors. Cancer Res 69(21):8491–8498, Epub 2009/10/22

    PubMed  CAS  Google Scholar 

  106. Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K et al (2000) BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res 60(21):6171–6177, Epub 2000/11/21

    PubMed  CAS  Google Scholar 

  107. Muchardt C, Yaniv M (2001) When the SWI/SNF complex remodels…the cell cycle. Oncogene 20(24):3067–3075, Epub 2001/06/23

    PubMed  CAS  Google Scholar 

  108. Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J et al (2008) Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mutat 29(5):617–622, Epub 2008/04/05

    PubMed  CAS  Google Scholar 

  109. Cheng SW, Davies KP, Yung E, Beltran RJ, Yu J, Kalpana GV (1999) c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nat Genet 22(1):102–105, Epub 1999/05/13

    PubMed  CAS  Google Scholar 

  110. Reisman DN, Sciarrotta J, Wang W, Funkhouser WK, Weissman BE (2003) Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res 63(3):560–566, Epub 2003/02/05

    PubMed  CAS  Google Scholar 

  111. Decristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE (2001) Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies. J Cell Physiol 186(1):136–145, Epub 2001/01/09

    PubMed  CAS  Google Scholar 

  112. Hill DA, Chiosea S, Jamaluddin S, Roy K, Fischer AH, Boyd DD et al (2004) Inducible changes in cell size and attachment area due to expression of a mutant SWI/SNF chromatin remodeling enzyme. J Cell Sci 117(Pt 24):5847–5854, Epub 2004/11/13

    PubMed  CAS  Google Scholar 

  113. Becker TM, Haferkamp S, Dijkstra MK, Scurr LL, Frausto M, Diefenbach E et al (2009) The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a. Mol Cancer 8:4, Epub 2009/01/20

    PubMed  Google Scholar 

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Acknowledgements

The authors are grateful for financial support from the SGC, a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Pfizer, Eli Lilly, Takeda, AbbVie, the Novartis Research Foundation, Boehringer Ingelheim, the Ontario Ministry of Research and Innovation and the Wellcome Trust. We apologise to the researchers that we were not able to cite as a result of space constraints.

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  1. Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Medical Sciences Division, University of Oxford, Oxford, Oxon, OX3 7DQ, UK

    Susanne Müller Ph.D., Hannah Lingard M.Sci., M.A.(Cantab.), D.Phil.(Oxon.) & Stefan Knapp Ph.D.

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  1. Susanne Müller Ph.D.
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  2. Hannah Lingard M.Sci., M.A.(Cantab.), D.Phil.(Oxon.)
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  3. Stefan Knapp Ph.D.
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    Rakesh Kumar

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Müller, S., Lingard, H., Knapp, S. (2014). Selective Inhibition of Acetyl-Lysine Effector Domains of the Bromodomain Family in Oncology. In: Kumar, R. (eds) Nuclear Signaling Pathways and Targeting Transcription in Cancer. Cancer Drug Discovery and Development. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-8039-6_11

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