Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma

Child's Nervous System volume 34, pages1497–1509(2018)Cite this article

Abstract

Purpose

Histone deacetylate inhibitors (HDACi), as valproic acid (VA), have been reported to enhance efficacy and to prevent drug resistance in some tumors, including medulloblastoma (MB). In the present study, we investigated VA role, combined to cisplatin (CDDP) in cell viability and gene expression of MB cell lines.

Methods

Dose-response curve determined IC50 values for each treatment: (1) VA single, (2) CDDP single, and (3) VA and CDDP combined. Cytotoxicity and flow cytometry evaluated cell viability after exposure to treatments. Quantitative PCR evaluated gene expression levels of AKT, CTNNB1, GLI1, KDM6A, KDM6B, NOTCH2, PTCH1, and TERT, before and after treatment. Besides, we performed next-generation sequencing (NGS) for PTCH1, TERT, and TP53 genes.

Results

The most effective treatment to reduce viability was combined for D283MED and ONS-76; and CDDP single for DAOY cells (p < 0.0001). TERT, GLI1, and AKT genes were overexpressed after treatments with VA. D283MED and ONS-76 cells presented variants in TERT and PTCH1, respectively and DAOY cell line presented a TP53 mutation.

Conclusions

MB tumors belonging to SHH molecular subgroup, with TP53MUT, would be the ones that present high risk in relation to VA use during the treatment, while TP53WT MBs can benefit from VA therapy, both SHH and groups 3 and 4. Our study shows a new perspective about VA action in medulloblastoma cells, raising the possibility that VA may act in different patterns. According to the genetic background of MB cell, VA can stimulate cell cycle arrest and apoptosis or induce resistance to treatment via signaling pathways activation.

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References

  1. 1.

    Crawford JR, MacDonald TJ, Packer RJ (2007) Medulloblastoma in childhood: new biological advances. Lancet Neurol 6(12):1073–1085

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Massimino M, Biassoni V, Gandola L, Garrè ML, Gatta G, Giangaspero F, Poggi G, Rutkowski S (2016) Childhood medulloblastoma. Crit Rev Oncol Hematol 105:35–51

    Article  PubMed  Google Scholar 

  3. 3.

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    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(4):465–472

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, Kool M, Dufour C, Vassal G, Milde T, Witt O, von Hoff K, Pietsch T, Northcott PA, Gajjar A, Robinson GW, Padovani L, André N, Massimino M, Pizer B, Packer R, Rutkowski S, Pfister SM, Taylor MD, Pomeroy SL (2016) Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 131(6):821–831

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, Boyett JM (1999) Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol 17(7):2127–2136

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    von Hoff K et al (2009) Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT’91. Eur J Cancer 45(7):1209–1217

    Article  Google Scholar 

  8. 8.

    von Hoff K, Rutkowski S (2012) Medulloblastoma. Curr Treat Options Neurol 14(4):416–426

    Article  Google Scholar 

  9. 9.

    Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, Giangaspero F, Ellison DW, Garre ML, Biassoni V, Grundy RG, Finlay JL, Dhall G, Raquin MA, Grill J (2010) Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28(33):4961–4968

    Article  PubMed  Google Scholar 

  10. 10.

    Ceccacci E, Minucci S (2016) Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia. Br J Cancer 114(6):605–611

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Hacker S et al (2011) Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation. Oncogene 30(19):2275–2281

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Gottlicher M et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Sun L, Moritake T, Zheng YW, Suzuki K, Gerelchuluun A, Hong Z, Zenkoh J, Taniguchi H, Tsuboi K (2013) In vitro stemness characterization of radio-resistant clones isolated from a medulloblastoma cell line ONS-76. J Radiat Res 54(1):61–69

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Ranger A, McDonald W, Moore E, DelMaestro R (2010) The invasiveness of five medulloblastoma cell lines in collagen gels. J Neuro-Oncol 96(2):181–189

    Article  CAS  Google Scholar 

  15. 15.

    Garzia L et al (2018) A hematogenous route for medulloblastoma leptomeningeal metastases. Cell 172(5):1050–1062.e14

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Furchert SE, Lanvers-Kaminsky C, Juürgens H, Jung M, Loidl A, Frühwald 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(8):1787–1794

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC (2005) Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther 4(12):1912–1922

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    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(3):887–895

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Shu Q, Antalffy B, Su JMF, Adesina A, Ou CN, Pietsch T, Blaney SM, Lau CC, Li XN (2006) Valproic acid prolongs survival time of severe combined immunodeficient mice bearing intracerebellar orthotopic medulloblastoma xenografts. Clin Cancer Res 12(15):4687–4694

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Patties I, Kortmann RD, Menzel F, Glasow A (2016) Enhanced inhibition of clonogenic survival of human medulloblastoma cells by multimodal treatment with ionizing irradiation, epigenetic modifiers, and differentiation-inducing drugs. J Exp Clin Cancer Res 35(1):94

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Cook D, Brown D, Alexander R, March R, Morgan P, Satterthwaite G, Pangalos MN (2014) Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nat Rev Drug Discov 13(6):419–431

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Ivanov DP, Coyle B, Walker DA, Grabowska AM (2016) In vitro models of medulloblastoma: choosing the right tool for the job. J Biotechnol 236:10–25

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Barallon R, Bauer SR, Butler J, Capes-Davis A, Dirks WG, Elmore E, Furtado M, Kline MC, Kohara A, Los GV, MacLeod RAF, Masters JRW, Nardone M, Nardone RM, Nims RW, Price PJ, Reid YA, Shewale J, Sykes G, Steuer AF, Storts DR, Thomson J, Taraporewala Z, Alston-Roberts C, Kerrigan L (2010) Recommendation of short tandem repeat profiling for authenticating human cell lines, stem cells, and tissues. In Vitro Cell Dev Biol Anim 46(9):727–732

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Cosme B, Falagan-Lotsch P, Ribeiro M, Napoleão K, Granjeiro JM, Moura-Neto R (2017) Are your results valid? Cellular authentication a need from the past, an emergency on the present. In Vitro Cell Dev Biol Anim 53:430–434

    Article  PubMed  Google Scholar 

  26. 26.

    Zanini C, Ercole E, Mandili G, Salaroli R, Poli A, Renna C, Papa V, Cenacchi G, Forni M (2013) Medullospheres from DAOY, UW228 and ONS-76 cells: increased stem cell population and proteomic modifications. PLoS One 8(5):e63748

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152(5):1065–1076

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Lee JH, Choy ML, Ngo L, Foster SS, Marks PA (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci U S A 107(33):14639–14644

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Chen CS, Wang YC, Yang HC, Huang PH, Kulp SK, Yang CC, Lu YS, Matsuyama S, Chen CY, Chen CS (2007) Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Res 67(11):5318–5327

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Abreu PA, Dellamora-Ortiz G, Leão-Ferreira LR, Gouveia M, Braggio E, Zalcberg I, Santos DO, Bourguinhon S, Cabral LM, Rodrigues CR, Castro HC (2008) DNA methylation: a promising target for the twenty-first century. Expert Opin Ther Targets 12(8):1035–1047

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K (2009) Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138(5):1019–1031

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Buchwald M, Kramer OH, Heinzel T (2009) HDACi—targets beyond chromatin. Cancer Lett 280(2):160–167

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Soussi T, Beroud C (2001) Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1(3):233–240

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, Smyth MJ, Johnstone RW (2001) The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of bid and production of reactive oxygen species. Proc Natl Acad Sci U S A 98(19):10833–10838

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Sonnemann J, Hartwig M, Plath A, Saravana Kumar K, Müller C, Beck JF (2006) Histone deacetylase inhibitors require caspase activity to induce apoptosis in lung and prostate carcinoma cells. Cancer Lett 232(2):148–160

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Lindemann RK, Newbold A, Whitecross KF, Cluse LA, Frew AJ, Ellis L, Williams S, Wiegmans AP, Dear AE, Scott CL, Pellegrini M, Wei A, Richon VM, Marks PA, Lowe SW, Smyth MJ, Johnstone RW (2007) Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. Proc Natl Acad Sci U S A 104(19):8071–8076

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Kool M, Jones DT, Jäger 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, König R, Beroukhim R, Bergthold G, van Sluis P, Volckmann R, Koster J, Versteeg R, Schmidt S, Wolf S, Lawerenz C, Bartholomae CC, von Kalle C, Unterberg A, Herold-Mende C, Hofer S, Kulozik AE, von Deimling A, Scheurlen W, Felsberg J, Reifenberger G, Hasselblatt M, Crawford JR, Grant GA, Jabado N, Perry A, Cowdrey C, Croul S, Zadeh G, Korbel JO, Doz F, Delattre O, Bader GD, McCabe M, Collins VP, Kieran MW, Cho YJ, Pomeroy SL, Witt O, Brors B, Taylor MD, Schüller U, Korshunov A, Eils R, Wechsler-Reya RJ, Lichter P, Pfister SM, ICGC PedBrain Tumor Project (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25(3):393–405

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJH, Martin DC, Castelo-Branco P, Baskin B, Ray PN, Bouffet E, von Bueren AO, Jones DTW, Northcott PA, Kool M, Sturm D, Pugh TJ, Pomeroy SL, Cho YJ, Pietsch T, Gessi M, Rutkowski S, Bognar L, Klekner A, Cho BK, Kim SK, Wang KC, Eberhart CG, Fevre-Montange M, Fouladi M, French PJ, Kros M, Grajkowska WA, Gupta N, Weiss WA, Hauser P, Jabado N, Jouvet A, Jung S, Kumabe T, Lach B, Leonard JR, Rubin JB, Liau LM, Massimi L, Pollack IF, Shin Ra Y, van Meir EG, Zitterbart K, Schüller U, Hill RM, Lindsey JC, Schwalbe EC, Bailey S, Ellison DW, Hawkins C, Malkin D, Clifford SC, Korshunov A, Pfister S, Taylor MD, Tabori U (2013) Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 31(23):2927–2935

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Kool M, Korshunov A, Remke M, Jones DTW, 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, Bäcklund 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(4):473–484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    Fujiki R, Sato A, Fujitani M, Yamashita T (2013) A proapoptotic effect of valproic acid on progenitors of embryonic stem cell-derived glutamatergic neurons. Cell Death Dis 4(6):e677

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Catalano MG, Fortunati N, Pugliese M, Costantino L, Poli R, Bosco O, Boccuzzi G (2005) Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab 90(3):1383–1389

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Yagi Y, Fushida S, Harada S, Kinoshita J, Makino I, Oyama K, Tajima H, Fujita H, Takamura H, Ninomiya I, Fujimura T, Ohta T, Yashiro M, Hirakawa K (2010) Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line. J Exp Clin Cancer Res 29:149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Jung EM, Choi YU, Kang HS, Yang H, Hong EJ, An BS, Yang JY, Choi KH, Jeung EB (2015) Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol 35(2):205–218

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Bajbouj K, Mawrin C, Hartig R, Schulze-Luehrmann J, Wilisch-Neumann A, Roessner A, Schneider-Stock R (2012) P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells. J Neuro-Oncol 107(3):503–516

    Article  CAS  Google Scholar 

  45. 45.

    Henderson C, Mizzau M, Paroni G, Maestro R, Schneider C, Brancolini C (2003) Role of caspases, bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). J Biol Chem 278(14):12579–12589

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T (2013) Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 16(1):91–103

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G (1997) Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 57(13):2581–2585

    PubMed  CAS  Google Scholar 

  49. 49.

    Juengel E, Makarević J, Tsaur I, Bartsch G, Nelson K, Haferkamp A, Blaheta RA (2013) Resistance after chronic application of the HDAC-inhibitor valproic acid is associated with elevated Akt activation in renal cell carcinoma in vivo. PLoS One 8(1):e53100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1):12–27

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Prof. Dr. Reinado Salomão and Milena Brunialti, from Department of Medicine-Imunology, Laboratory of Imunology - Federal University of São Paulo, that made available cell-flow analysis equipment BD LSRFortessa™ (BD Biosciences®), and FlowJo® software.

Funding

FAPESP (Fundação de Amparo à Pesquisa do Estado de Sao Paulo) project number 2013/12281-4, and Pediatric Oncology Institute – IOP/GRAACC.

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Affiliations

  1. Pediatrics Oncology Institute-GRAACC (Grupo de Apoio ao Adolescente e à Criança com Câncer) /UNIFESP (Federal University of Sao Paulo), Rua Botucatu, 743, Floor 8 – Genetics Laboratory, Vila Clementino, São Paulo, SP, Zip Code 04023-062, Brazil

    Bruna Mascaro-Cordeiro, Indhira Dias Oliveira, Francine Tesser-Gamba, Nasjla Saba-Silva, Sergio Cavalheiro, Patrícia Dastoli & Silvia Regina Caminada Toledo

  2. Department of Morphology and Genetics, Division of Genetics, Federal University of São Paulo, São Paulo, SP, Brazil

    Bruna Mascaro-Cordeiro & Silvia Regina Caminada Toledo

  3. Departament of Neurology, Federal University of Sao Paulo, Sao Paulo, SP, Brazil

    Lorena Favaro Pavon & Sergio Cavalheiro

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  1. Bruna Mascaro-Cordeiro
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  2. Indhira Dias Oliveira
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Correspondence to Silvia Regina Caminada Toledo.

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Mascaro-Cordeiro, B., Oliveira, I.D., Tesser-Gamba, F. et al. Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma. Childs Nerv Syst 34, 1497–1509 (2018). https://doi.org/10.1007/s00381-018-3817-7

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Keywords

  • Medulloblastoma
  • HDACi
  • NGS
  • Gene expression
  • TP53