title: NCYM is upregulated by lncUSMycN and modulates N-Myc expression.
abstract: Neuroblastoma is the most common solid tumor in early childhood. Patients with neuroblastoma due to the amplification of a 130-kb genomic DNA region containing the MYCN, MYCN antisense NCYM and lncUSMycN genes show poor prognosis. BET bromodomain inhibitors show anticancer efficacy against neuroblastoma partly by reducing MYCN gene transcription and N-Myc mRNA and protein expression. We have previously shown that the long nocoding RNA lncUSMycN upregulates N-Myc mRNA expression by binding to the RNA-binding protein NonO. In this study, we found that lncUSMycN upregulated NCYM expression, and knocking-down lncUSMycN reduced histone H3 lysine 4 trimethylation, a marker for active gene transcription, at the NCYM gene promoter. NCYM upregulated N-Myc mRNA expression, NCYM RNA formed a complex with NonO protein, and knocking down NCYM expression reduced neuroblastoma cell proliferation. Importantly, treatment with BET bromodomain inhibitors reduced NCYM expression. In human neuroblastoma patients, high levels of NCYM expression in tumor tissues correlated with high levels of N-Myc, NonO and lncUSMycN expression as well as poor patient prognosis. Taken together, our findings suggest that lncUSMycN upregulates NCYM expression by activating its gene transcription, and that NCYM RNA upregulates N-Myc mRNA expression by binding to NonO. Our findings also provide further evidence for the application of BET bromodomain inhibitors for the therapy of neuroblastoma characterized by MYCN/NCYM gene locus amplification.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, NSW 2031, Australia.
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, NSW 2031, Australia.
authors.forename: Bernard
authors.initials: B
authors.lastname: Atmadibrata
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, NSW 2031, Australia.
authors.forename: Sujanna
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, NSW 2031, Australia.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Tee
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, NSW 2031, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
mesh_terms: D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology*; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D050810:Octamer Transcription Factors / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D004268:DNA-Binding Proteins; C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D006657:Histones; C000588908:MYCNOS protein, human; C083214:NONO protein, human; D009363:Neoplasm Proteins; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014230:Triazoles