BET Inhibition Silences Expression of MYCN and BCL2 and Induces Cytotoxicity in Neuroblastoma Tumor Models

PLoS ONE

Volumn 8, Issue 8, 2013, Pages

  Wyce, Anastasia ^a   Ganji, Gopinath ^a   Smitheman, Kimberly N ^a   Chung, Chun wa ^b   Korenchuk, Susan ^a   Bai, Yuchen ^a   Barbash, Olena ^a   Le, BaoChau ^a   Craggs, Peter D ^b   McCabe, Michael T ^a   Kennedy Wilson, Karen M ^a   Sanchez, Lydia V ^a   Gosmini, Romain L ^c   Parr, Nigel ^b   McHugh, Charles F ^a   Dhanak, Dashyant ^a   Prinjha, Rab K ^b   Auger, Kurt R ^a   Tummino, Peter J ^a  

^a GLAXOSMITHKLINE   (United States)

^b GLAXOSMITHKLINE   (United Kingdom)

^c GLAXOSMITHKLINE   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BET PROTEIN; GSK 1324726A; TUMOR PROTEIN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; BET GENE; CANCER INHIBITION; CONTROLLED STUDY; DOWN REGULATION; DRUG CYTOTOXICITY; DRUG EFFECT; DRUG POTENCY; DRUG STRUCTURE; FEMALE; GENE DOSAGE; GENE EXPRESSION REGULATION; GENE FUNCTION; GENE REPRESSION; GENE SILENCING; GENETIC ANALYSIS; INHIBITION KINETICS; MOUSE; NEUROBLASTOMA; NEUROBLASTOMA CELL; NONHUMAN; ONCOGENE MYC; PROTO ONCOGENE; SIGNAL TRANSDUCTION; TUMOR GENE;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BENZODIAZEPINES; CELL PROLIFERATION; CLUSTER ANALYSIS; DISEASE MODELS, ANIMAL; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE REGULATORY NETWORKS; GENE SILENCING; HUMANS; KINETICS; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; NEUROBLASTOMA; NUCLEAR PROTEINS; ONCOGENE PROTEINS; PROTEIN BINDING; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS C-BCL-2; RNA-BINDING PROTEINS; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TUMOR BURDEN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84883012780     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0072967     Document Type: Article

References (51)

1. Rodríguez-Paredes M, Esteller M, (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17: 330-339. PubMed: 21386836.
2. Jenuwein T, Allis CD, (2001) Translating the histone code. Science 293: 1074-1080. doi:10.1126/science.1063127. PubMed: 11498575.
3. Florence B, Faller DV, (2001) You bet-cha: a novel family of transcriptional regulators. Front Biosci 6: D1008-D1018. doi:10.2741/Florence. PubMed: 11487468.
4. Dey A, Nishiyama A, Karpova T, McNally J, Ozato K, (2009) Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol Biol Cell 20: 4899-4909. doi:10.1091/mbc.E09-05-0380. PubMed: 19812244.
5. Yang Z, He N, Zhou Q, (2008) Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol 28: 967-976. doi:10.1128/MCB.01020-07. PubMed: 18039861.
6. Denis GV, Vaziri C, Guo N, Faller DV, (2000) RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F. Cell Growth Differ 11: 417-424. PubMed: 10965846.
7. Denis GV, McComb ME, Faller DV, Sinha A, Romesser PB, et al. (2006) Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines. J Proteome Res 5: 502-511. doi:10.1021/pr050430u. PubMed: 16512664.
8. Jones MH, Numata M, Shimane M, (1997) Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics 45: 529-534. doi:10.1006/geno.1997.5000. PubMed: 9367677.
9. LeRoy G, Rickards B, Flint SJ, (2008) The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell 30: 51-60. doi:10.1016/j.molcel.2008.01.018. PubMed: 18406326.
10. Chung CW, Coste H, White JH, Mirguet O, Wilde J, et al. (2011) Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem 54: 3827-3838. doi:10.1021/jm200108t. PubMed: 21568322.
11. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, et al. (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478: 529-533. doi:10.1038/nature10509. PubMed: 21964340.
12. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, et al. (2010) Selective inhibition of BET bromodomains. Nature 468: 1067-1073. doi:10.1038/nature09504. PubMed: 20871596.
13. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, et al. (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468: 1119-1123. doi:10.1038/nature09589. PubMed: 21068722.
14. Prinjha RK, Witherington J, Lee K, (2012) Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol Sci 33: 146-153. doi:10.1016/j.tips.2011.12.002. PubMed: 22277300.
15. French CA, (2010) NUT midline carcinoma. Cancer Genet Cytogenet 203: 16-20. doi:10.1016/j.cancergencyto.2010.06.007. PubMed: 20951314.
16. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, et al. (2011) RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478: 524-528. doi:10.1038/nature10334. PubMed: 21814200.
17. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, et al. (2011) Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A 108: 16669-16674. doi:10.1073/pnas.1108190108. PubMed: 21949397.
18. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, et al. (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146: 904-917. doi:10.1016/j.cell.2011.08.017. PubMed: 21889194.
19. Ott CJ, Kopp N, Bird L, Paranal RM, Qi J, et al. (2012) BET bromodomain inhibition targets both c-MYC and IL7R in high-risk acute lymphoblastic leukemia. Blood, 120: 2843-52. PubMed: 22904298.
20. Albihn A, Johnsen JI, Henriksson MA, (2010) MYC in oncogenesis and as a target for cancer therapies. Adv Cancer Res 107: 163-224. doi:10.1016/S0065-230X(10)07006-5. PubMed: 20399964.
21. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, et al. (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463: 899-905. doi:10.1038/nature08822. PubMed: 20164920.
22. Vita M, Henriksson M, (2006) The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 16: 318-330. doi:10.1016/j.semcancer.2006.07.015. PubMed: 16934487.
23. Darnell JE Jr., (2002) Transcription factors as targets for cancer therapy. Nat Rev Cancer 2: 740-749. doi:10.1038/nrc906. PubMed: 12360277.
24. Chen QR, Song YK, Yu LR, Wei JS, Chung JY, et al. (2010) Global genomic and proteomic analysis identifies biological pathways related to high-risk neuroblastoma. J Proteome Res 9: 373-382. doi:10.1021/pr900701v. PubMed: 19921788.
25. Fredlund E, Ringnér M, Maris JM, Påhlman S, (2008) High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A 105: 14094-14099. doi:10.1073/pnas.0804455105. PubMed: 18780787.
26. Raetz EA, Kim MK, Moos P, Carlson M, Bruggers C, et al. (2003) Identification of genes that are regulated transcriptionally by Myc in childhood tumors. Cancer 98: 841-853. doi:10.1002/cncr.11584. PubMed: 12910530.
27. Wang Y, Sugiyama H, Axelson H, Panda CK, Babonits M, et al. (1992) Functional homology between N-myc and c-myc in murine plasmacytomagenesis: plasmacytoma development in N-myc transgenic mice. Oncogene 7: 1241-1247. PubMed: 1375720.
28. Malynn BA, de Alboran IM, O'Hagan RC, Bronson R, Davidson L, et al. (2000) N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. Genes Dev 14: 1390-1399. PubMed: 10837031.
29. Zeller KI, Jegga AG, Aronow BJ, O'Donnell KA, Dang CV, (2003) An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol 4: R69. doi:10.1186/gb-2003-4-10-r69. PubMed: 14519204.
30. Reed JC, Meister L, Tanaka S, Cuddy M, Yum S, et al. (1991) Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin. Cancer Res 51: 6529-6538. PubMed: 1742726.
31. Castle VP, Heidelberger KP, Bromberg J, Ou X, Dole M, et al. (1993) Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol 143: 1543-1550. PubMed: 8256847.
32. Maris JM, Hogarty MD, Bagatell R, Cohn SL, (2007) Neuroblastoma. Lancet 369: 2106-2120. doi:10.1016/S0140-6736(07)60983-0. PubMed: 17586306.
33. 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 U S A 109: 19408-19413. doi:10.1073/pnas.1216363109. PubMed: 23129625.
34. Cheng Z, Gong Y, Ma Y, Lu K, Lu X, et al. (2013) Inhibition of BET Bromodomain Targets Genetically Diverse Glioblastoma. Clin Cancer Res, 19: 1748-59. PubMed: 23403638.
35. Jiang R, Xue S, Jin Z, (2011) Stable knockdown of MYCN by lentivirus-based RNAi inhibits human neuroblastoma cells growth in vitro and in vivo. Biochem Biophys Res Commun 410: 364-370. doi:10.1016/j.bbrc.2011.06.020. PubMed: 21683062.
36. Galderisi U, Di BG, Cipollaro M, Peluso G, Cascino A, et al. (1999) Differentiation and apoptosis of neuroblastoma cells: role of N-myc gene product. J Cell Biochem 73: 97-105. doi:10.1002/(SICI)1097-4644(19990401)73:1. PubMed: 10088728.
37. Strieder V, Lutz W, (2003) E2F proteins regulate MYCN expression in neuroblastomas. J Biol Chem 278: 2983-2989. doi:10.1074/jbc.M207596200. PubMed: 12438307.
38. Valentijn LJ, Koster J, Haneveld F, Aissa RA, van Sluis P, et al. (2012) Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. Proc Natl Acad Sci U S A 109: 19190-19195. doi:10.1073/pnas.1208215109. PubMed: 23091029.
39. Godfried MB, Veenstra M, Sluis P, Boon K, Asperen R, et al. (2002) The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. Oncogene 21: 2097-2101. doi:10.1038/sj.onc.1205259. PubMed: 11960382.
40. Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, et al. (2013) Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition. Cancer Discov.
41. Lamers F, Schild L, den Hartog IJ, Ebus ME, Westerhout EM, et al. (2012) Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer, 48: 3093-103. PubMed: 22366560.
42. Dole M, Nuñez G, Merchant AK, Maybaum J, Rode CK, et al. (1994) Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res 54: 3253-3259. PubMed: 8205548.
43. van Golen CM, Castle VP, Feldman EL, (2000) IGF-I receptor activation and BCL-2 overexpression prevent early apoptotic events in human neuroblastoma. Cell Death Differ 7: 654-665. doi:10.1038/sj.cdd.4400693. PubMed: 10889510.
44. Lestini BJ, Goldsmith KC, Fluchel MN, Liu X, Chen NL, et al. (2009) Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists. Cancer Biol Ther 8: 1587-1595. doi:10.4161/cbt.8.16.8964. PubMed: 19556859.
45. Jasty R, van Golen C, Lin HJ, Solomon G, Heidelberger K, et al. (2001) Bcl-2 and M-Myc coexpression increases IGF-IR and features of malignant growth in neuroblastoma cell lines. Neoplasia 3: 304-313. doi:10.1038/sj.neo.7900171. PubMed: 11571630.
46. Brambilla E, Negoescu A, Gazzeri S, Lantuejoul S, Moro D, et al. (1996) Apoptosis-related factors p53, Bcl2, and Bax in neuroendocrine lung tumors. Am J Pathol 149: 1941-1952. PubMed: 8952529.
47. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, et al. (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492: 108-112. doi:10.1038/nature11606. PubMed: 23051747.
48. Vindeløv LL, Christensen IJ, Nissen NI, (1983) A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry 3: 323-327. doi:10.1002/cyto.990030503. PubMed: 6188586.
49. Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, et al. (2006) GenePattern. Nat Genet 2. 0: 38: 500-501.
50. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102: 15545-15550. doi:10.1073/pnas.0506580102. PubMed: 16199517.
51. Clements EG, Mohammad HP, Leadem BR, Easwaran H, Cai Y, et al. (2012) DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes. Nucleic Acids Res, 40: 4334-46. PubMed: 22278882.