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

Schulte, Johannes H; Lim, Soyoung; Schramm, Alexander; Friedrichs, Nicolaus; Koster, Jan; Versteeg, Rogier; Øra, Ingrid LU ; Pajtler, Kristian; Klein-Hitpass, Ludger and Kuhfittig-Kulle, Steffi, et al. (2009) In Cancer Research 69. p.2065-2071
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... (More)
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]. (Less)
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published
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Cancer Research
volume
69
pages
2065 - 2071
publisher
American Association for Cancer Research
external identifiers
  • WOS:000263937800049
  • PMID:19223552
  • Scopus:62449197931
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-1735
language
English
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yes
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d6e73b0f-8033-4d09-b7f2-fbed9ca42773 (old id 1302469)
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http://www.ncbi.nlm.nih.gov/pubmed/19223552?dopt=Abstract
date added to LUP
2009-03-03 11:51:46
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2016-11-06 04:26:18
@misc{d6e73b0f-8033-4d09-b7f2-fbed9ca42773,
  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. [Cancer Res 2009;69(5):2065-71].},
  author       = {Schulte, Johannes H and Lim, Soyoung and Schramm, Alexander and Friedrichs, Nicolaus and Koster, Jan and Versteeg, Rogier and Øra, Ingrid and Pajtler, Kristian and Klein-Hitpass, Ludger and Kuhfittig-Kulle, Steffi and Metzger, Eric and Schüle, Roland and Eggert, Angelika and Buettner, Reinhard and Kirfel, Jutta},
  issn         = {1538-7445},
  language     = {eng},
  pages        = {2065--2071},
  publisher    = {ARRAY(0x8575df8)},
  series       = {Cancer Research},
  title        = {Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-08-1735},
  volume       = {69},
  year         = {2009},
}