ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis

F. Galeano, C. Rossetti, S. Tomaselli, L. Cifaldi, M. Lezzerini, M. Pezzullo, R. Boldrini, L. Massimi, C. M. Di Rocco, F. Locatelli, A. Gallo

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)998-1009
Number of pages12
JournalOncogene
Volume32
Issue number8
DOIs
Publication statusPublished - Feb 21 2013

Fingerprint

Glioblastoma
Astrocytoma
RNA Editing
Growth
S-Phase Kinase-Associated Proteins
Neoplasms
Poisons
RNA Precursors
Brain
Tumor Suppressor Genes
Phosphoric Monoester Hydrolases
Cell Cycle
Cell Line
Enzymes
Genes
Proteins
immune RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. / Galeano, F.; Rossetti, C.; Tomaselli, S.; Cifaldi, L.; Lezzerini, M.; Pezzullo, M.; Boldrini, R.; Massimi, L.; Di Rocco, C. M.; Locatelli, F.; Gallo, A.

In: Oncogene, Vol. 32, No. 8, 21.02.2013, p. 998-1009.

Research output: Contribution to journalArticle

Galeano, F. ; Rossetti, C. ; Tomaselli, S. ; Cifaldi, L. ; Lezzerini, M. ; Pezzullo, M. ; Boldrini, R. ; Massimi, L. ; Di Rocco, C. M. ; Locatelli, F. ; Gallo, A. / ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. In: Oncogene. 2013 ; Vol. 32, No. 8. pp. 998-1009.
@article{fedd6592c1b34deca4043acc3fdc74a6,
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.",
author = "F. Galeano and C. Rossetti and S. Tomaselli and L. Cifaldi and M. Lezzerini and M. Pezzullo and R. Boldrini and L. Massimi and {Di Rocco}, {C. M.} and F. Locatelli and A. Gallo",
year = "2013",
month = "2",
day = "21",
doi = "10.1038/onc.2012.125",
language = "English",
volume = "32",
pages = "998--1009",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis

AU - Galeano, F.

AU - Rossetti, C.

AU - Tomaselli, S.

AU - Cifaldi, L.

AU - Lezzerini, M.

AU - Pezzullo, M.

AU - Boldrini, R.

AU - Massimi, L.

AU - Di Rocco, C. M.

AU - Locatelli, F.

AU - Gallo, A.

PY - 2013/2/21

Y1 - 2013/2/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84874768382&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874768382&partnerID=8YFLogxK

U2 - 10.1038/onc.2012.125

DO - 10.1038/onc.2012.125

M3 - Article

VL - 32

SP - 998

EP - 1009

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 8

ER -