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

Abstract

Aberrant epigenetic changes are hallmarks of most cancers. Recently, a new class of histone modifying enzymes, demethylases, was identified catalyzing the removal of methyl groups from histone H3 lysine residues. Here, we address the functional significance of 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. LSD1 inhibition using monoamine oxidase inhibitors resulted in an increase of global H3K4 methylation, growth inhibition of neuroblastoma cells in vitro and reduced xenograft growth in vivo. To prove specificity of LSD1 targeting therapy in vivo, a transgenic mouse for tetracycline inducible expression of a shRNA against LSD1 was generated. This model is now used to simulate therapeutic LSD1 inhibition in vivo. Here, we provide first evidence that a histone demethylase, LSD1, is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells. Our results suggest that targeting histone demethylases may provide a novel option for cancer therapy.