title: Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma.
abstract: The chromatin-modifying enzyme lysine-specific demethylase 1, KDM1A/LSD1 is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells and its overexpression correlated with aggressive disease, poor differentiation and infaust outcome. Here, we show that LSD1 physically binds MYCN both in vitro and in vivo and that such an interaction requires the MYCN BoxIII. We found that LSD1 co-localizes with MYCN on promoter regions of CDKN1A/p21 and Clusterin (CLU) suppressor genes and cooperates with MYCN to repress the expression of these genes. KDM1A needs to engage with MYCN in order to associate with the CDKN1A and CLU promoters. The expression of CLU and CDKN1A can be restored in MYCN-amplified cells by pharmacological inhibition of LSD1 activity or knockdown of its expression. Combined pharmacological inhibition of MYCN and LSD1 through the use of small molecule inhibitors synergistically reduces MYCN-amplified Neuroblastoma cell viability in vitro. These findings demonstrate that LSD1 is a critical co-factor of the MYCN repressive function, and suggest that combination of LSD1 and MYCN inhibitors may have strong therapeutic relevance to counteract MYCN-driven oncogenesis.
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.|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 Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Milazzo
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Sorrentino
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: Giacomo
authors.initials: G
authors.lastname: Di Palo
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 Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.|CIRI Health Sciences and Technologies (HST), Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Majello
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D056466:Histone Demethylases; D008239:Lysine
keywords: LSD1; MYCN; neuroblastoma; transcription