title: Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy.
abstract: Aberrant epigenetic changes in DNA methylation and histone acetylation are hallmarks of most cancers, whereas histone methylation was previously considered to be irreversible and less versatile. Recently, several histone demethylases were identified catalyzing the removal of methyl groups from histone H3 lysine residues and thereby influencing gene expression. Neuroblastomas continue to remain a clinical challenge despite advances in multimodal therapy. Here, we address the functional significance of the chromatin-modifying enzyme lysine-specific demethylase 1 (LSD1) in neuroblastoma. LSD1 expression correlated with adverse outcome and was inversely correlated with differentiation in neuroblastic tumors. Differentiation of neuroblastoma cells resulted in down-regulation of LSD1. Small interfering RNA-mediated knockdown of LSD1 decreased cellular growth, induced expression of differentiation-associated genes, and increased target gene-specific H3K4 methylation. Moreover, LSD1 inhibition using monoamine oxidase inhibitors resulted in an increase of global H3K4 methylation and growth inhibition of neuroblastoma cells in vitro. Finally, targeting LSD1 reduced neuroblastoma xenograft growth in vivo. Here, we provide the first evidence that a histone demethylase, LSD1, is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells. We show that inhibition of LSD1 reprograms the transcriptome of neuroblastoma cells and inhibits neuroblastoma xenograft growth. Our results suggest that targeting histone demethylases may provide a novel option for cancer therapy.
authors.affiliation: Department of Paediatric Oncology and Hematology, University Children's Hospital Essen, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lim
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ora
authors.forename: Kristian
authors.initials: K
authors.lastname: Pajtler
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Steffi
authors.initials: S
authors.lastname: Kuhfittig-Kulle
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D056466:Histone Demethylases; D006801:Humans; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D008996:Monoamine Oxidase Inhibitors; D034741:RNA, Small Interfering; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating