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Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy

¹ Department of Paediatric Oncology and Hematology, University Children's Hospital Essen; ² Institute of Cell Biology, University Hospital of Essen, Essen, Germany; ³ Institute of Pathology, University of Bonn, Bonn, Germany; ⁴ Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; ⁵ Department of Pediatric Oncology and Hematology, Lund University Hospital, Lund, Sweden; ⁶ Center for Clinical Research, Freiburg University Medical Center, Freiburg, Germany

Requests for reprints: Jutta Kirfel, Institute of Pathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany. Phone: 49-228-28719247; Fax: 49-228-28715030; E-mail: Jutta.Kirfel{at}ukb.uni-bonn.de.

Key Words: LSD1 • Neuroblastoma

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. [Cancer Res 2009;69(5):2065–71]

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