title: The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma.
abstract: BACKGROUND
  Medulloblastoma is a leading cause of childhood cancer-related deaths. Current aggressive treatments frequently lead to cognitive and neurological disabilities in survivors. Novel targeted therapies are required to improve outcome in high-risk medulloblastoma patients and quality of life of survivors. Targeting enzymes controlling epigenetic alterations is a promising approach recently bolstered by the identification of mutations in histone demethylating enzymes in medulloblastoma sequencing efforts. Hypomethylation of lysine 4 in histone 3 (H3K4) is also associated with a dismal prognosis for medulloblastoma patients. Functional characterization of important epigenetic key regulators is urgently needed.
  
  
  RESULTS
  We examined the role of the H3K4 modifying enzyme, KDM1A, in medulloblastoma, an enzyme also associated with malignant progression in the closely related tumor, neuroblastoma. Re-analysis of gene expression data and immunohistochemistry of tissue microarrays of human medulloblastomas showed strong KDM1A overexpression in the majority of tumors throughout all molecular subgroups. Interestingly, KDM1A knockdown in medulloblastoma cell lines not only induced apoptosis and suppressed proliferation, but also impaired migratory capacity. Further analyses revealed bone morphogenetic protein 2 (BMP2) as a major KDM1A target gene. BMP2 is known to be involved in development and differentiation of granule neuron precursor cells (GNCPs), one potential cell of origin for medulloblastoma. Treating medulloblastoma cells with the specific KDM1A inhibitor, NCL-1, significantly inhibited growth in vitro.
  
  
  CONCLUSIONS
  We provide the first evidence that a histone demethylase is functionally involved in the regulation of the malignant phenotype of medulloblastoma cells, and lay a foundation for future evaluation of KDM1A-inihibiting therapies in combating medulloblastoma.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany. kristian.pajtler@uk-essen.de.
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Pajtler
authors.forename: Christina
authors.initials: C
authors.lastname: Weingarten
authors.forename: Theresa
authors.initials: T
authors.lastname: Thor
authors.forename: Annette
authors.initials: A
authors.lastname: Künkele
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.forename: Michael
authors.initials: M
authors.lastname: Grotzer
authors.forename: Anja
authors.initials: A
authors.lastname: Rieb
authors.forename: Annika
authors.initials: A
authors.lastname: Sprüssel
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008822:Mice, Transgenic; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
chemical_list: C562353:2-(3-(3-benzamido-4-(benzylamino)-4-oxobutoxy)phenyl)cyclopropylamine; C525718:BMP2 protein, human; D001549:Benzamides; D055396:Bone Morphogenetic Protein 2; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating