title: LSD1 mediates MYCN control of epithelial-mesenchymal transition through silencing of metastatic suppressor NDRG1 gene.
abstract: Neuroblastoma (NB) with MYCN amplification is a highly aggressive and metastatic tumor in children. The high recurrence rate and resistance of NB cells to drugs urgently demands a better therapy for this disease. We have recently found that MYCN interacts with the lysine-specific demethylase 1 (LSD1), a histone modifier that participates in key aspects of gene transcription. In cancer cells, LSD1 contributes to the genetic reprogramming that underlies to Epithelial-Mesenchymal Transition (EMT) and tumor metastasis. Here, we show that LSD1 affects motility and invasiveness of NB cells by modulating the transcription of the metastasis suppressor NDRG1 (N-Myc Downstream-Regulated Gene 1). At mechanistic level, we found that LSD1 co-localizes with MYCN at the promoter region of the NDRG1 gene and inhibits its expression. Pharmacological inhibition of LSD1 relieves repression of NDRG1 by MYCN and affects motility and invasiveness of NB cells. These effects were reversed by overexpressing NDRG1. In NB tissues, high levels of LSD1 correlate with low levels of NDRG1 and reduced patients survival. Collectively, our findings elucidate a mechanism of how MYCN/LSD1 control motility and invasiveness of NB cells through transcription regulation of NDRG1 expression and suggest that pharmacological targeting of LSD1 represents a valuable approach for NB therapy.
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Ambrosio
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples, 'Federico II', Naples, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Amente
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Carmen D
authors.initials: CD
authors.lastname: Saccà
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples, 'Federico II', Naples, Italy.|CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy.
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples, 'Federico II', Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Lania
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Majello
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D056466:Histone Demethylases; D047908:Intracellular Signaling Peptides and Proteins; D000071447:N-Myc Proto-Oncogene Protein; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C459801:MYCN protein, human; C495195:KDM1A protein, human
keywords: EMT; LSD1; MYCN; NDRG1; neuroblastoma