MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

• Published in: The Journal of clinical investigation Vol. 123; no. 6; pp. 2703 - 2718
• Main Authors: Nemlich, Yael, Greenberg, Eyal, Ortenberg, Rona, Besser, Michal J, Barshack, Iris, Jacob-Hirsch, Jasmine, Jacoby, Elad, Eyal, Eran, Rivkin, Ludmila, Prieto, Victor G, Chakravarti, Nitin, Duncan, Lyn M, Kallenberg, David M, Galun, Eitan, Bennett, Dorothy C, Amariglio, Ninette, Bar-Eli, Menashe, Schachter, Jacob, Rechavi, Gideon, Markel, Gal
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2013
• Subjects: Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Analysis; Animals; Apoptosis; Binding Sites; Biomedical research; Brain research; Cell Line, Tumor; Cell Proliferation; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Development and progression; DNA Methylation; Down-Regulation; Editing; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Growth; Humans; Male; Medical research; Melanoma; Melanoma - metabolism; Melanoma - secondary; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Mutation; Neoplasm Transplantation; Physiological aspects; Pregnancy Proteins - genetics; Proteins; Proteins - genetics; Proteins - metabolism; Ribonuclease III - genetics; Ribonuclease III - metabolism; RNA Editing; RNA Interference; RNA-Binding Proteins; Science; Skin cancer; Transcriptome; Tumors; United States; Israel
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci62980

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.