title: MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth.
abstract: Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding–dependent, yet RNA editing–independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.
authors.affiliation: Ella Institute of Melanoma, Ramat-Gan, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Nemlich
authors.forename: Eyal
authors.initials: E
authors.lastname: Greenberg
authors.forename: Rona
authors.initials: R
authors.lastname: Ortenberg
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Elad
authors.initials: E
authors.lastname: Jacoby
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.forename: Ludmila
authors.initials: L
authors.lastname: Rivkin
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Nitin
authors.initials: N
authors.lastname: Chakravarti
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.forename: David M
authors.initials: DM
authors.lastname: Kallenberg
authors.forename: Eitan
authors.initials: E
authors.lastname: Galun
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011257:Pregnancy Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017393:RNA Editing; D034622:RNA Interference; D016601:RNA-Binding Proteins; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: C474043:DGCR8 protein, human; C524941:MIRN17 microRNA, human; C582553:MIRN432 microRNA, human; D035683:MicroRNAs; D011257:Pregnancy Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C579465:RTL1 protein, human; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D053487:DEAD-box RNA Helicases