title: ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.
abstract: Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post-transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs.
authors.affiliation: Laboratorio di RNA Editing, Oncohaematology Department, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Galeano
authors.forename: C
authors.initials: C
authors.lastname: Rossetti
authors.forename: S
authors.initials: S
authors.lastname: Tomaselli
authors.forename: L
authors.initials: L
authors.lastname: Cifaldi
authors.forename: M
authors.initials: M
authors.lastname: Lezzerini
authors.forename: M
authors.initials: M
authors.lastname: Pezzullo
authors.forename: R
authors.initials: R
authors.lastname: Boldrini
authors.forename: L
authors.initials: L
authors.lastname: Massimi
authors.forename: C M
authors.initials: CM
authors.lastname: Di Rocco
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.forename: A
authors.initials: A
authors.lastname: Gallo
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001254:Astrocytoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016601:RNA-Binding Proteins; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C474200:CDC14B protein, human; D054637:Dual-Specificity Phosphatases; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase