Top

Published in:

Open Access 01-12-2015 | Research

Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Authors: Jonas Ecker, Ina Oehme, Ralph Mazitschek, Andrey Korshunov, Marcel Kool, Thomas Hielscher, Judit Kiss, Florian Selt, Carina Konrad, Marco Lodrini, Hedwig E Deubzer, Andreas von Deimling, Andreas E Kulozik, Stefan M Pfister, Olaf Witt, Till Milde

Published in: Acta Neuropathologica Communications | Issue 1/2015

Abstract

Introduction

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs.

Material and Methods

Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed.

Results

HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds.

Conclusions

We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration.

Available only for authorised users

Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J (2014) CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011. Neuro-Oncology 16 Suppl 4:iv1–iv63, doi: 10.1093/neuonc/nou223CrossRefPubMed

Kaatsch P, Spix C (2013) German Childhood Cancer Registry - Report 2012 (1980-2012), Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz

Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472, doi: 10.1007/s00401-011-0922-zCrossRefPubMedCentralPubMed

Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stutz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD et al (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105, doi: 10.1038/nature11284CrossRefPubMedCentralPubMed

Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM (2012) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12:818–834, doi: 10.1038/nrc3410CrossRefPubMedCentralPubMed

Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:1408–1414, doi: 10.1200/JCO.2009.27.4324CrossRefPubMed

Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, Lau CC, Olson JM, Gilbertson RJ, Gajjar A, Delattre O, Kool M, Ligon K, Meyerson M, Mesirov JP, Pomeroy SL (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424–1430, doi: 10.1200/JCO.2010.28.5148CrossRefPubMedCentralPubMed

Shih DJ, Northcott PA, Remke M, Korshunov A, Ramaswamy V, Kool M, Luu B, Yao Y, Wang X, Dubuc AM, Garzia L, Peacock J, Mack SC, Wu X, Rolider A, Morrissy AS, Cavalli FM, Jones DT, Zitterbart K, Faria CC, Schuller U, Kren L, Kumabe T, Tominaga T, Shin Ra Y, Garami M, Hauser P, Chan JA, Robinson S, Bognar L et al (2014) Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32:886–896, doi: 10.1200/JCO.2013.50.9539CrossRefPubMedCentralPubMed

Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, Milde T, Bourdeaut F, Ryzhova M, Sturm D, Pfaff E, Stark S, Hutter S, Seker-Cin H, Johann P, Bender S, Schmidt C, Rausch T, Shih D, Reimand J, Sieber L, Wittmann A, Linke L, Witt H, Weber UD, Zapatka M et al (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25:393–405, doi: 10.1016/j.ccr.2014.02.004CrossRefPubMed

10.

Northcott PA, Lee C, Zichner T, Stutz AM, Erkek S, Kawauchi D, Shih DJ, Hovestadt V, Zapatka M, Sturm D, Jones DT, Kool M, Remke M, Cavalli FM, Zuyderduyn S, Bader GD, VandenBerg S, Esparza LA, Ryzhova M, Wang W, Wittmann A, Stark S, Sieber L, Seker-Cin H, Linke L, Kratochwil F, Jager N, Buchhalter I, Imbusch CD, Zipprich G et al (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428–434, doi: 10.1038/nature13379CrossRefPubMed

11.

Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD et al (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488:106–110, doi: 10.1038/nature11329CrossRefPubMedCentralPubMed

12.

Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, Chalhoub N, Baker SJ, Huether R, Kriwacki R, Curley N, Thiruvenkatam R, Wang J, Wu G, Rusch M, Hong X, Becksfort J, Gupta P, Ma J, Easton J, Vadodaria B, Onar-Thomas A, Lin T, Li S, Pounds S, Paugh S et al (2012) Novel mutations target distinct subgroups of medulloblastoma. Nature 488:43–48, doi: 10.1038/nature11213CrossRefPubMedCentralPubMed

13.

Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Backlund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM (2012) Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 123:473–484, doi: 10.1007/s00401-012-0958-8CrossRefPubMedCentralPubMed

14.

Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD et al (2012) Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488:49–56, doi: 10.1038/nature11327CrossRefPubMedCentralPubMed

15.

Jones DT, Northcott PA, Kool M, Pfister SM (2013) The role of chromatin remodeling in medulloblastoma. Brain Pathol 23:193–199, doi: 10.1111/bpa.12019CrossRefPubMed

16.

Dubuc AM, Remke M, Korshunov A, Northcott PA, Zhan SH, Mendez-Lago M, Kool M, Jones DT, Unterberger A, Morrissy AS, Shih D, Peacock J, Ramaswamy V, Rolider A, Wang X, Witt H, Hielscher T, Hawkins C, Vibhakar R, Croul S, Rutka JT, Weiss WA, Jones SJ, Eberhart CG, Marra MA, Pfister SM, Taylor MD (2013) Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol 125:373–384, doi: 10.1007/s00401-012-1070-9CrossRefPubMedCentralPubMed

17.

Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, Northcott PA, Sultan M, Stachurski K, Ryzhova M, Warnatz HJ, Ralser M, Brun S, Bunt J, Jager N, Kleinheinz K, Erkek S, Weber UD, Bartholomae CC, von Kalle C, Lawerenz C, Eils J, Koster J, Versteeg R, Milde T, Witt O, Schmidt S, Wolf S, Pietsch T, Rutkowski S, Scheurlen W et al (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510:537–541, doi: 10.1038/nature13268CrossRefPubMed

18.

Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784, doi: 10.1038/nrd2133CrossRefPubMed

19.

Lee SJ, Lindsey S, Graves B, Yoo S, Olson JM, Langhans SA (2013) Sonic hedgehog-induced histone deacetylase activation is required for cerebellar granule precursor hyperplasia in medulloblastoma. PLoS One 8:e71455, doi: 10.1371/journal.pone.0071455CrossRefPubMedCentralPubMed

20.

Jaboin J, Wild J, Hamidi H, Khanna C, Kim CJ, Robey R, Bates SE, Thiele CJ (2002) MS-27-275, an Inhibitor of Histone Deacetylase, Has Marked in Vitro and in Vivo Antitumor Activity against Pediatric Solid Tumors. Cancer Res 62:6108–6115PubMed

21.

Furchert SE, Lanvers-Kaminsky C, Juurgens H, Jung M, Loidl A, Fruhwald MC (2007) Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. Int J Cancer 120:1787–1794, doi: 10.1002/ijc.22401CrossRefPubMed

22.

Wegener D, Deubzer HE, Oehme I, Milde T, Hildmann C, Schwienhorst A, Witt O (2008) HKI 46F08, a novel potent histone deacetylase inhibitor, exhibits antitumoral activity against embryonic childhood cancer cells. Anti-Cancer Drugs 19:849–857, doi: 10.1097/CAD.0b013e32830efbebCrossRefPubMed

23.

Ecke I, Petry F, Rosenberger A, Tauber S, Monkemeyer S, Hess I, Dullin C, Kimmina S, Pirngruber J, Johnsen SA, Uhmann A, Nitzki F, Wojnowski L, Schulz-Schaeffer W, Witt O, Hahn H (2009) Antitumor effects of a combined 5-aza-2′deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res 69:887–895, doi: 10.1158/0008-5472.CAN-08-0946CrossRefPubMed

24.

Milde T, Lodrini M, Savelyeva L, Korshunov A, Kool M, Brueckner LM, Antunes AS, Oehme I, Pekrun A, Pfister SM, Kulozik AE, Witt O, Deubzer HE (2012) HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neuro-Oncol 110:335–348, doi: 10.1007/s11060-012-0978-1CrossRef

25.

Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, Fischer M, Witt O (2009) Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 15:91–99, doi: 10.1158/1078-0432.CCR-08-0684CrossRefPubMed

26.

Oehme I, Linke JP, Bock BC, Milde T, Lodrini M, Hartenstein B, Wiegand I, Eckert C, Roth W, Kool M, Kaden S, Grone HJ, Schulte JH, Lindner S, Hamacher-Brady A, Brady NR, Deubzer HE, Witt O (2013) Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl Acad Sci U S A 110:E2592–E2601, doi: 10.1073/pnas.1300113110CrossRefPubMedCentralPubMed

27.

Lodrini M, Oehme I, Schroeder C, Milde T, Schier MC, Kopp-Schneider A, Schulte JH, Fischer M, De Preter K, Pattyn F, Castoldi M, Muckenthaler MU, Kulozik AE, Westermann F, Witt O, Deubzer HE (2013) MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma. Nucleic Acids Res 41:6018–6033, doi: 10.1093/nar/gkt346CrossRefPubMedCentralPubMed

28.

Fabian J, Lodrini M, Oehme I, Schier MC, Thole TM, Hielscher T, Kopp-Schneider A, Opitz L, Capper D, von Deimling A, Wiegand I, Milde T, Mahlknecht U, Westermann F, Popanda O, Roels F, Hero B, Berthold F, Fischer M, Kulozik AE, Witt O, Deubzer HE (2014) GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3. Cancer Res 74:2604–2616, doi: 10.1158/0008-5472.CAN-13-1904CrossRefPubMed

29.

Milde T, Oehme I, Korshunov A, Kopp-Schneider A, Remke M, Northcott P, Deubzer HE, Lodrini M, Taylor MD, von Deimling A, Pfister S, Witt O (2010) HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res 16:3240–3252, doi: 10.1158/1078-0432.CCR-10-0395CrossRefPubMed

30.

Ecker J, Witt O, Milde T (2013) Targeting of histone deacetylases in brain tumors. CNS Oncol 2:359–376, doi: 10.2217/cns.13.24CrossRefPubMed

31.

Tessier P, Smil DV, Wahhab A, Leit S, Rahil J, Li Z, Deziel R, Besterman JM (2009) Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors. Bioorg Med Chem Lett 19:5684–5688, doi: 10.1016/j.bmcl.2009.08.010CrossRefPubMed

32.

Bai AH, Milde T, Remke M, Rolli CG, Hielscher T, Cho YJ, Kool M, Northcott PA, Jugold M, Bazhin AV, Eichmuller SB, Kulozik AE, Pscherer A, Benner A, Taylor MD, Pomeroy SL, Kemkemer R, Witt O, Korshunov A, Lichter P, Pfister SM (2012) MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma. Acta Neuropathol 123:529–538, doi: 10.1007/s00401-011-0924-xCrossRefPubMed

33.

Schmitt M, Pawlita M (2009) High-throughput detection and multiplex identification of cell contaminations. Nucleic Acids Res 37:e119, doi: 10.1093/nar/gkp581CrossRefPubMedCentralPubMed

34.

Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, Eberhart CG, Dubuc A, Guettouche T, Cardentey Y, Bouffet E, Pomeroy SL, Marra M, Malkin D, Rutka JT, Korshunov A, Pfister S, Taylor MD (2012) Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol 123:615–626, doi: 10.1007/s00401-011-0899-7CrossRefPubMedCentralPubMed

35.

Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G, Rutkowski S, Schick M, Bewerunge-Hudler M, Korshunov A, Lichter P, Taylor MD, Pfister SM, Jones DT (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916, doi: 10.1007/s00401-013-1126-5CrossRefPubMedCentralPubMed

36.

Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, Jones DT, Northcott PA, Garzia L, Bertrand KC, Wittmann A, Yao Y, Roberts SS, Massimi L, Van Meter T, Weiss WA, Gupta N, Grajkowska W, Lach B, Cho YJ, von Deimling A, Kulozik AE, Witt O, Bader GD, Hawkins CE, Tabori U et al (2011) Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20:143–157, doi: 10.1016/j.ccr.2011.07.007CrossRefPubMedCentralPubMed

37.

Milde T, Hielscher T, Witt H, Kool M, Mack SC, Deubzer HE, Oehme I, Lodrini M, Benner A, Taylor MD, von Deimling A, Kulozik AE, Pfister SM, Witt O, Korshunov A (2012) Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol 22:848–860, doi: 10.1111/j.1750-3639.2012.00600.xCrossRefPubMed

38.

Rizzardi AE, Johnson AT, Vogel RI, Pambuccian SE, Henriksen J, Skubitz AP, Metzger GJ, Schmechel SC (2012) Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring. Diagn Pathol 7:42, doi: 10.1186/1746-1596-7-42CrossRefPubMedCentralPubMed

39.

Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A (2009) Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27:1627–1636, doi: 10.1200/JCO.2008.17.9432CrossRefPubMed

40.

Milde T, Kleber S, Korshunov A, Witt H, Hielscher T, Koch P, Kopp HG, Jugold M, Deubzer HE, Oehme I, Lodrini M, Grone HJ, Benner A, Brustle O, Gilbertson RJ, von Deimling A, Kulozik AE, Pfister SM, Martin-Villalba A, Witt O (2011) A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta Neuropathol 122:637–650, doi: 10.1007/s00401-011-0866-3CrossRefPubMedCentralPubMed

41.

Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R (2010) Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6:238–243, doi: 10.1038/nchembio.313CrossRefPubMedCentralPubMed

42.

Fakih MG, Fetterly G, Egorin MJ, Muindi JR, Espinoza-Delgado I, Zwiebel JA, Litwin A, Holleran JL, Wang K, Diasio RB (2010) A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors. Clin Cancer Res 16:3786–3794, doi: 10.1158/1078-0432.CCR-10-0547CrossRefPubMedCentralPubMed

43.

Kummar S, Gutierrez M, Gardner ER, Donovan E, Hwang K, Chung EJ, Lee MJ, Maynard K, Kalnitskiy M, Chen A, Melillo G, Ryan QC, Conley B, Figg WD, Trepel JB, Zwiebel J, Doroshow JH, Murgo AJ (2007) Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res 13:5411–5417, doi: 10.1158/1078-0432.CCR-07-0791CrossRefPubMed

44.

Rathkopf DE, Picus J, Hussain A, Ellard S, Chi KN, Nydam T, Allen-Freda E, Mishra KK, Porro MG, Scher HI, Wilding G (2013) A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 72:537–544, doi: 10.1007/s00280-013-2224-8CrossRefPubMedCentralPubMed

45.

Sherman EJ, Su YB, Lyall A, Schoder H, Fury MG, Ghossein RA, Haque S, Lisa D, Shaha AR, Tuttle RM, Pfister DG (2013) Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine-refractory thyroid carcinoma. Thyroid 23:593–599, doi: 10.1089/thy.2012.0393CrossRefPubMedCentralPubMed

46.

Vansteenkiste J, Van Cutsem E, Dumez H, Chen C, Ricker JL, Randolph SS, Schoffski P (2008) Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Investig New Drugs 26:483–488, doi: 10.1007/s10637-008-9131-6CrossRef

47.

Woyach JA, Kloos RT, Ringel MD, Arbogast D, Collamore M, Zwiebel JA, Grever M, Villalona-Calero M, Shah MH (2009) Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab 94:164–170, doi: 10.1210/jc.2008-1631CrossRefPubMedCentralPubMed

48.

Molife LR, de Bono JS (2011) Belinostat: clinical applications in solid tumors and lymphoma. Expet Opin Investig Drugs 20:1723–1732, doi: 10.1517/13543784.2011.629604CrossRef

49.

Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931, doi: 10.1200/JCO.2005.14.167CrossRefPubMedCentralPubMed

50.

Chou CJ, Herman D, Gottesfeld JM (2008) Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J Biol Chem 283:35402–35409, doi: 10.1074/jbc.M807045200CrossRefPubMedCentralPubMed

51.

Lahm A, Paolini C, Pallaoro M, Nardi MC, Jones P, Neddermann P, Sambucini S, Bottomley MJ, Lo Surdo P, Carfi A, Koch U, De Francesco R, Steinkuhler C, Gallinari P (2007) Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci U S A 104:17335–17340, doi: 10.1073/pnas.0706487104CrossRefPubMedCentralPubMed

52.

Jones P, Altamura S, De Francesco R, Gallinari P, Lahm A, Neddermann P, Rowley M, Serafini S, Steinkuhler C (2008) Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases. Bioorg Med Chem Lett 18:1814–1819, doi: 10.1016/j.bmcl.2008.02.025CrossRefPubMed

53.

Zhang CL, McKinsey TA, Lu JR, Olson EN (2001) Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J Biol Chem 276:35–39, doi: 10.1074/jbc.M007364200CrossRefPubMed

54.

Gregoire S, Yang XJ (2005) Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol Cell Biol 25:2273–2287, doi: 10.1128/MCB. 25.6.2273-2287.2005CrossRefPubMedCentralPubMed

55.

McKinsey TA, Zhang CL, Lu J, Olson EN (2000) Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408:106–111, doi: 10.1038/35040593CrossRefPubMed

56.

Kao HY, Verdel A, Tsai CC, Simon C, Juguilon H, Khochbin S (2001) Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J Biol Chem 276:47496–47507, doi: 10.1074/jbc.M107631200CrossRefPubMed

57.

Graham C, Tucker C, Creech J, Favours E, Billups CA, Liu T, Fouladi M, Freeman BB 3rd, Stewart CF, Houghton PJ (2006) Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo. Clin Cancer Res 12:223–234, doi: 10.1158/1078-0432.CCR-05-1225CrossRefPubMed

58.

Bhandari DR, Seo KW, Jung JW, Kim HS, Yang SR, Kang KS (2011) The regulatory role of c-MYC on HDAC2 and PcG expression in human multipotent stem cells. J Cell Mol Med 15:1603–1614, doi: 10.1111/j.1582-4934.2010.01144.xCrossRefPubMed

59.

Prinz F, Schlange T, Asadullah K (2011) Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov 10:712, doi: 10.1038/nrd3439-c1CrossRefPubMed

60.

Begley CG, Ellis LM (2012) Drug development: Raise standards for preclinical cancer research. Nature 483:531–533, doi: 10.1038/483531aCrossRefPubMed

61.

Smith MA, Houghton P (2013) A proposal regarding reporting of in vitro testing results. Clin Cancer Res 19:2828–2833, doi: 10.1158/1078-0432.CCR-13-0043CrossRefPubMedCentralPubMed

62.

Khan O, Fotheringham S, Wood V, Stimson L, Zhang C, Pezzella F, Duvic M, Kerr DJ, La Thangue NB (2010) HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc Natl Acad Sci U S A 107:6532–6537, doi: 10.1073/pnas.0913912107CrossRefPubMedCentralPubMed

63.

Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, Boyer M, Mo FK, Koh J, Rha SY, Hui EP, Jeung HC, Roh JK, Yu SC, To KF, Tao Q, Ma BB, Chan AW, Tong JH, Erlichman C, Chan AT, Goh BC (2012) Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol 30:3361–3367, doi: 10.1200/JCO.2011.41.2395CrossRefPubMedCentralPubMed

64.

Lu H, Tonge PJ (2010) Drug-target residence time: critical information for lead optimization. Curr Opin Chem Biol 14:467–474, doi: 10.1016/j.cbpa.2010.06.176CrossRefPubMedCentralPubMed

65.

Lauffer BE, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, Flicke B, Ritscher A, Fedorowicz G, Vallero R, Ortwine DF, Gunzner J, Modrusan Z, Neumann L, Koth CM, Lupardus PJ, Kaminker JS, Heise CE, Steiner P (2013) Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J Biol Chem 288:26926–26943, doi: 10.1074/jbc.M113.490706CrossRefPubMedCentralPubMed

Title: Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma
Authors: Jonas Ecker
Ina Oehme
Ralph Mazitschek
Andrey Korshunov
Marcel Kool
Thomas Hielscher
Judit Kiss
Florian Selt
Carina Konrad
Marco Lodrini
Hedwig E Deubzer
Andreas von Deimling
Andreas E Kulozik
Stefan M Pfister
Olaf Witt
Till Milde
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-015-0201-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Abstract

Introduction

Material and Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Material and Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients

Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau

Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis

The A673T mutation in the amyloid precursor protein reduces the production of β-amyloid protein from its β-carboxyl terminal fragment in cells

Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease

Neuron-to-neuron α-synuclein propagation in vivo is independent of neuronal injury