A-to-I RNA editing and cancer: from pathology to basic science.
ABSTRACT In eukaryotes mRNA transcripts are extensively processed by different post-transcriptional events such as alternative splicing and RNA editing in order to generate many different mRNAs from the same gene, increasing the transcriptome and then the proteome. The most frequent RNA editing mechanism in mammals involves the conversion of specific adenosines into inosines by the ADAR family of enzymes. This editing event can change both the sequence and the secondary structure of RNA molecules, with important consequences on both the final proteins and regulatory RNAs. Alteration in RNA editing has been connected to numerous human pathologies and recent studies have demonstrated its importance in tumor progression.
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ABSTRACT: In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed "seed" sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A-to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Specifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a* and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a* promoted glioma cell migration and invasion, while the edited miR-376a* suppressed these features. The effects of the unedited miR-376a* were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumor-dependent introduction of a single base difference in the miR-376a* sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a* as a potential therapeutic target in glioblastoma cells.The Journal of clinical investigation 10/2012; · 15.39 Impact Factor
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ABSTRACT: Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that converts adenosine (A) to inosine (I), and essential for normal development. In this study, we reported an essential role of ADAR1 in the survival and maintenance of intestinal stem cells and intestinal homoeostasis by suppressing endoplasmic reticulum (ER) stress and interferon (IFN) signaling. ADAR1 was highly expressed in the Lgr5+ cells, and its deletion in adult mice led to a rapid apoptosis and loss of these actively cycling stem cells in the small intestine and colon. ADAR1 deletion resulted in a drastic expansion of progenitors and Paneth cells but a reduction of three other major epithelial lineages. Moreover, loss of ADAR1 induced ER stress and activation of IFN signaling, and altered expression in WNT targets, followed by intestinal inflammation. An ER stress inhibitor partially suppressed crypt apoptosis. Finally, data from cultured intestinal crypts demonstrated that loss of ADAR1 in the epithelial cells is the primary cause of these effects. These results support an essential role of ADAR1 and RNA editing in tissue homeostasis and stem cells.Cell Death & Disease 01/2013; 4:e599. · 6.04 Impact Factor
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ABSTRACT: The Hedgehog (HH) signaling pathway has important roles in tumorigenesis and in embryonal patterning. The Glioma-associated oncogene 1 (GLI1) is a key molecule in HH signaling, acting as a transcriptional effector and, moreover, is considered to be a potential therapeutic target for several types of cancer. To extend our previous focus on the implications of alternative splicing for HH signal transduction, we now report on an additional post-transcriptional mechanism with an impact on GLI1 activity, namely RNA editing. The GLI1 mRNA is highly edited at nucleotide 2179 by adenosine deamination in normal cerebellum, but the extent of this modification is reduced in cell lines from the cerebellar tumor medulloblastoma. Additionally, basal cell carcinoma tumor samples exhibit decreased GLI1 editing compared with normal skin. Interestingly, knocking down of either ADAR1 or ADAR2 reduces RNA editing of GLI1. This adenosine to inosine substitution leads to a change from Arginine to Glycine at position 701 that influences not only GLI1 transcriptional activity, but also GLI1-dependent cellular proliferation. Specifically, the edited GLI1, GLI1-701G, has a higher capacity to activate most of the transcriptional targets tested and is less susceptible to inhibition by the negative regulator of HH signaling suppressor of fused. However, the Dyrk1a kinase, implicated in cellular proliferation, is more effective in increasing the transcriptional activity of the non-edited GLI1. Finally, introduction of GLI1-701G into medulloblastoma cells confers a smaller increase in cellular growth relative to GLI1. In conclusion, our findings indicate that RNA editing of GLI1 is a regulatory mechanism that modulates the output of the HH signaling pathway.RNA biology 01/2013; 10(2). · 5.56 Impact Factor
© 2009 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
In eukaryotes mRNA transcripts are extensively processed by
different post-transcriptional events such as alternative splicing and
RNA editing in order to generate many different mRNAs from the
same gene, increasing the transcriptome and then the proteome.
The most frequent RNA editing mechanism in mammals involves
the conversion of specific adenosines into inosines by the ADAR
family of enzymes. This editing event can change both the sequence
and the secondary structure of RNA molecules, with important
consequences on both the final proteins and regulatory RNAs.
Alteration in RNA editing has been connected to numerous human
pathologies and recent studies have demonstrated its importance in
Several post-transcriptional mechanisms have been recognized
that guide the production of multiple RNAs from a single gene.
Among these the most studied is the alternative splicing that acts
on almost 70% of the transcripts in mammals.1,2 Another post-
transcriptional mechanism is RNA editing.3,4 RNA editing can
generally be defined as any site-specific alteration in the RNA
sequence copied from the DNA or RNA template excluding changes
due to capping, splicing and polyadenylation.3,4 Both splicing and
editing increase the number of different RNA molecules in a cell
as they produce a mixture of modified and non-modified RNAs
(Fig. 1). However an important difference exists between these two
mechanisms: splicing adds or removes blocks of sequences “defined”
by the DNA, whereas RNA editing changes the nucleotides coded by
the genome, re-coding or correcting the genomic information. The
best-characterized type of RNA editing found in mammals converts
cytosine (C) into uracil (U) and adenosine (A) into inosine (I).
In humans the most frequent type of RNA editing is the conver-
sion of adenosine into inosine within a dsRNA structure by the
ADARs, Adenosine DeAminases that act on double-stranded RNAs.
[RNA Biology 5:3, 135-139; July/August/September 2008]; ©2008 Landes Bioscience
This point of view article summarizes our current knowledge
regarding the different biological roles of A-to-I RNA editing due to
ADAR enzymes and its importance in tumors.
ADARs and their Activity
ADARs have a common domain structure that is comprised of
two or three RNA binding domains (RBDs) at the amino terminus
and a highly conserved deaminase domain (DM) at the carboxy
terminus (Fig. 2). ADAR enzymes are generated in human by three
independent genes ADAR1-3 located respectively on chromosomes
1, 21 and 10. Several isoforms of these enzymes exist. In particular
ADAR1 is synthesized in two major isoforms, ADAR1 150-kDa
(cytoplasmatic isoform) and ADAR1 110-kDa (nuclear isoform),
due to the alternative initiation of transcription and starting codons
(Fig. 2). The crystal structure of the deaminase domain of the human
ADAR2 has recently been defined showing the presence of a small
molecule, inositol hexakisposphate (IP6), that works as an essen-
tial cofactor for the ADAR2 catalytic function.5 A-to-I editing on
dsRNA was discovered almost twenty years ago independently by
two groups and was described as an unwinding enzymatic activity.6,7
Inosine is interpreted as guanosine by the translation and splicing
machineries with a huge impact on transcriptome and proteome
variation. Moreover inosine does not pair with uracil but instead
with cytosine, changing the (A:U) base pair into an (I:U) mismatch
and this was the basis of the unwinding activity originally described.
In summary the conversion of adenosine into inosine can affect both
codon changes and RNA structures (Fig. 3).
It has been shown that RNA editing varies during differentiation
and in different cell types.8 The total amount of inosines was esti-
mated at a frequency of 1 in 17,000 nucleotides in rat brain mRNAs
and 1 in 33,000 nucleotides in rat heart.9 More recently it has been
demonstrated that most of the A-to-I substitutions occur not within
the coding portions of mRNAs but largely in non-coding RNAs.
This occurs particularly within the untraslated regions (UTRs) with
the 3'-UTRs showing almost 50% editing, the 5'-UTRs almost 15%
editing and introns almost 33% editing.10 The pre-mRNA untrans-
lated regions are characterised by a high presence of secondary
RNA structures and enriched in repetitive elements, mainly Alu
repeats,10-14 that represent good substrates for the ADAR proteins.
Point of View
A-to-I RNA editing and cancer
From pathology to basic science
Angela Gallo1,* and Silvia Galardi2
1RNA editing Lab; Ospedale Pediatrico Bambino Gesu; Rome, Italy; 2Department of Experimental Medicine and Biochemical Sciences; University of “Tor Vergata”; Rome, Italy
Abbreviations: ADAR, adenosine deaminase on dsRNA; RBD, RNA binding domain; CNS, central nervous system; dsRNA, double
stranded RNA; ssRNA, single stranded RNA; GBM, glioblastoma multiforme (astrocytoma grade IV)
Key words: ADARs, RNA editing, inosine, RNA binding protein, post-transcriptional regulation, cancer, astrocytomas, microRNA, GBM
*Correspondence to: Angela Gallo; RNA editing Lab; OPBG; Piazza S. Onofrio,4;
Rome, Italy; Tel.: +390668592658; Fax: +390668592904; Email: email@example.com
Submitted: 07/02/08; Accepted: 08/05/08
Previously published online as an RNA Biology E-publication:
© 2009 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
event was described in the protein tyrosine phosphatase transcript
ADAR alterations in cancer
136RNA Biology2008; Vol. 5 Issue 3
The phenomenon of A-to-I editing is far less abundant in mice, rats,
chickens and flies than in humans, which correlates with the relative
under-representation of Alu repeats in these non-primate genomes.15
RNA editing on non-coding RNA can affect the secondary (and
consequently the tertiary) structure of the RNAs and then modulate
and/or prevent RNA-protein and RNA-RNA interactions. RNA
editing on non-coding portions of the transcripts could influence
splicing, localization, stability and translation efficiency of the
The active ADAR enzymes (ADAR1 and ADAR2) are ubiqui-
tous proteins and their loss in mouse models produce phenotypes
incompatible with life.16,17 The extent of A-to-I editing can vary
dramatically between RNA substrates with some RNAs containing
only a single editing event whereas in others >50% of the adenosines
are modified.3 The editing activity of these enzymes
seems extremely well regulated in vivo.18-20 What
modulates the editing activity in vivo is still not
clear but it has been suggested that the sequence and
structure of the RNA substrate21,22 and the enzy-
matic core domain (DM) of the ADAR proteins23
are important. It has also been shown that ADAR
enzymes act co-transcriptionally and this observation
opens new intriguing questions regarding possible
interactions between ADARs and the transcription
machinery as well as with splicing factors.24 ADARs
can form homodimers and heterodimers25-27 with
a significant impact on editing activity.25 Finally it
has been shown that ADARs can interact with other
proteins such as the NF90 family of proteins that can
stimulate transcription and translation.28
All of the above observations emphasize the
complex scenario in which ADAR may play a major
role and underlines the possibility that ADARs activity could also be
modulated in vivo by interactions with other proteins. Cell-specific
and tissue-specific proteins that interact with ADARs could partially
explain differences in editing that exist in the same transcript
expressed in different tissues.
ADAR Alteration and Cancer
It is evident that proteins with the ability to convert nucleotides
could potentially be extremely dangerous if not well regulated in
their activity or expression levels. In mammals, Drosophila and
squid, most of the edited transcripts that guide an amino acid change
are expressed in the central nervous system (CNS). This opens an
intriguing question if such a large variety of different proteins gener-
ated by editing is necessary in the CNS or if it is just more tolerated
in the CNS because it is recognised as an immune-privileged system.
Diseases affecting the CNS have been reported with an alteration in
RNA editing such as depression, epilepsy, schizophrenia and amyo-
trophic lateral sclerosis (ALS) (reviewed in refs. 8 and 29). RNA
editing has also been found to be altered in tumors with different
laboratories having observed a general decrease in editing activity in
brain tumors.20,30-32 Moreover a recent study using a mainly bioin-
formatic approach demonstrated global hypoediting in different
Acute myeloid leukemia (AML). Originally an altered editing
Figure 1. Increasing the transcriptome by RNA editing. RNA editing pro-
duces a mixture of both unedited and edited RNAs. RNA editing generates
protein diversity as usually both the edited and unedited version of the pro-
tein are co-expressed in the same cell and the ratio between the two variants
can be regulated in a cell type-specific or time-dependent manner.
Figure 2. Schematic diagram of human ADAR. Human ADAR proteins are shown with double
stranded RNA binding domains (dsRBDs) in blue, the deaminase domain in green and the
ssRNA binding domain in ADAR3 in red. The ADAR1 mRNA is transcribed from an interferon-
inducible promoter that produced a full-length 150-kDa form of ADAR1 and a shorter 110-kDa
ADAR1 (by two different ATGs in frame). Two additional ADAR1 mRNAs both transcribed
from constitutive promoters direct the synthesis of the shorter 110-kDa ADAR1 protein.
Chromosomes are indicated where ADAR genes are localized.
Figure 3. Consequences of the RNA editing by ADAR enzymes. ADAR
enzymes fine-tune many biological pathways by changing both the pri-
mary sequence of mRNAs (changing codons and splicing patterns) and the
secondary structures of RNAs.
© 2009 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
ADAR alterations in cancer
www.landesbioscience.comRNA Biology 137
Hypoediting: a general phenomenon common in various tumor
tissues. Using mainly a bioinformatic approach it has been shown
recently that there is a global hypoediting of Alu repetitive elements
not only in brain tumors but also in different tumor tissues such as
prostate, lung, kidney and testis when compared with controls.30 The
authors showed an important correlation between a downregulation
of editing and the grade of malignancy of the tumors with editing
being lower in higher grade tumors. This observation underlined
for the first time a strong link between deregulation of ADARs and
cancer progression.30 The authors showed that the reduction of
ADAR3 mRNA level correlated with the grade of the tumor.30
The authors suggested that the decrease in editing activity in brain
tumors was due to a general decrease of expression of the mRNAs
levels of all the ADAR enzymes (ADAR1-3). However the analysis of
the BLCAP transcript at the Y/C site showed a higher editing activity
in tumors versus controls in brain, oral cavity and lung.30 Interesting
recent papers demonstrated that the Y/C site of the BLCAP has been
identified as an ADAR1 editing site.37,38
Importance of ADAR Substrates in Oncology
The understanding of how A-to-I editing is regulated in vivo,
is an issue that is just beginning to be investigated but it is critical
for the connection between ADARs and human pathologies.
Observations with respect to this show that both ADAR1 and
ADAR2 are co-expressed in a cell and this is important as ADAR
homodimers and hetrodimers are found to be present in different cell
types. We do not know if more than one mechanism exists in ADAR
de-regulation in tumors.20,30,33 Certainly a general downregulation
of ADAR2 activity seems a common feature that has been observed
in brain tumors by different laboratories.20,30,31
Many laboratories have put a big effort in trying to identify new
ADARs mRNA substrates13,39-42 that could have an important role
in tumor appearance and progression. Fascinatingly it has been
shown that ADARs can edit not only coding RNAs (pre-mRNAs)
but also non-coding RNAs such as microRNAs.43,44
MicroRNA, editing and cancer. As ADARs can act on both
perfect and imperfect dsRNA any RNA with such a characteristic
could be a hypothetical ADAR substrate. In fact it has been shown
that ADARs can modify not only pre-mRNA but other RNA catego-
ries such as viral RNA44,45 and a new class of small non-coding RNA,
the microRNAs and their precursor.44 MicroRNAs (or miRNAs) are
a class of small non-coding RNAs that function mainly as specific
repressors of protein-coding genes. In mammals miRNAs affect a
large number of signalling pathways and disturbance of their expres-
sion may play a role in the initiation and progression of certain
diseases including tumors.46
miRNAs are transcribed into primary transcripts (pri-miRNAs)
that undergo sequential processing by two members of the RNase
III family, Drosha in the nucleus and Dicer in the cytoplasm. These
two proteins recognize the foldback hairpin structure of the pri-
miRNA (Drosha) and the pre-miRNA (Dicer) to produce a 21–23
dsRNA mature miRNA. mature miRNA is then incorporated in a
ribonucleoprotein complex called RNA-induced silencing complex
(RISC)47 that target miRNA on the mRNA 3'-UTR. MiRNAs
downregulate gene expression by mRNA cleavage or translational
repression depending on the degree of complementarities between
the miRNA and the target mRNAs.47
in patients affected by acute myeloid leukemia.33 The protein
tyrosine phosphatase (PTPN6 or SHP-1, PTP1C, HPC) is recog-
nized as a tumor suppressor gene. PTPN6 transcripts isolated from
leukemic patients (CD34+/CD117+ blasts) showed an aberrant/
unusual editing event at one of its branch-sites that leads to a hypo-
thetical non-functional PTPN6 protein.33 The authors stressed the
possibility that this aberrant editing event only present in tumor
samples could be at the origin of this type of cancer. Intriguingly the
aberrant splicing of PTPN6 due to an editing alteration was lower
in patients at remission.33 It has been suggested that this is due to
defects in editing regulation rather than an increase in the deaminase
activity in these patients. However the authors did not identify which
enzyme was responsible for the alteration either ADAR1 or ADAR2
or if the aberrant editing observed was indeed responsible for the
cancerous cell transformation.
Glioblastoma multiforme. A decrease in RNA editing of the
GluR-B at the Q/R site (exclusively edited by ADAR2,16) was shown
in patients affected by glioblastoma multiforme (GBMs).31 Neoplasm
of glial cells represents the most common tumors of the CNS with
glioblastoma multiforme (or astrocytoma grade IV) being the most
aggressive form. The authors connected for the first time defects
of ADAR2 activity and cancer. However as tumors show frequent
alterations in several biological pathways the question remained open
if the loss of editing observed in these tumors was a consequence of,
or a key event for, the malignant cell transformation. Other work
by Ishiuki and co-authors showed that indeed the Q/R site of the
GluR-B is essential for suppressing migration in vivo in glioblastoma
cells.32 These authors showed that GluR2Q- assembling AMPA
receptors (under-edited form of GluR-B) are Ca+2 permeable chan-
nels and this may contribute to the invasive and aggressive growth
behaviour of glioblastomas through the Atk pathway activation.32,34
Pediatric astrocytomas at different grades of malignancy.
Currently there is little data available on RNA editing in children.
The histology of many pediatric astrocytomas (grade I–IV) is
similar to that of their adult counterparts but significant differences
do exist.35,36 A correlation between a decrease in ADAR2 editing
activity and grade of tumor malignancy (astrocytomas grade I–IV)
was demonstrated in children.20 Moreover differences have been
found between adult and pediatric tumors with the Q/R site of
GluR-B being less downregulated in pediatric GBMs (92–100%)
than their adult counterparts (70–95%).20,31 Both astrocytoma
tissues and astrocytoma cell lines showed little or no ADAR2 editing
activity. By restoring a correct ADAR2 editing level in astrocy-
toma cell lines we observed a significant decrease in cell malignant
behavior. Indeed ADAR2 activity was directly involved in both the
cell cycle, slowing down cell growth rate at the S-G2 phase, and cell
migration.20 ADAR2 was found to be normal in tumors however
a high-expression level of ADAR1 150 mRNA was observed in
the supra-tentorial astrocytomas.20 In tumors the high expression
of ADAR1 150 mRNA and the presence of a new splicing event
occurring in this transcript led to a high production of the nuclear
ADAR1 110-kDa protein. Interestingly ADAR1 110-kDa and
ADAR2 are both nuclear proteins. Indeed elevated levels of ADAR1
as found in astrocytomas interfere with ADAR2 editing activity.20
We proposed a model where a correct balance of ADARs is essential
for accurate editing and its alteration could be at the origin of cell
© 2009 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
ADAR alterations in cancer
138RNA Biology2008; Vol. 5 Issue 3
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Recent work revealed that the A-to-I modification by the ADAR
enzymes occurs in a number of different miRNAs.43,48-51 It was
estimated that about 20% of a mammal’s miRNAs are subjected
to editing (K. Nishikura personal communication). In addition as
ADARs can alter the sequence and structures of the 3'-UTR of many
transcripts, the impact of editing in micro RNA regulation could be
It has been shown that editing of pri- or pre-miRNAs could
modulate the expression levels of mature miRNAs by suppressing
their maturation pathways due to Dicer and Drosha. Editing on
pri-miR142 inhibits Drosha cleavage52 and editing of pri-miR151
inhibits Dicer cleavage.51 In both of these examples RNA editing
affects the final amount of the mature miRNAs. Alternatively
editing can also alter the sequence of mature miRNA as shown in
miR376a.50 The consequence is the silencing of a new set of genes
different from those targeted by the unedited miRNA. It was shown
that the endogenous expression of PRPS1 a predicted target of the
edited miR-376a, was dependent upon editing of miR-376a and the
editing activity of ADAR2.50
Thus editing may modulate the function of miRNAs by altering
the amount of, or the pairing between, miRNAs and their targets.
Interestingly a recent paper connected miR-376a with pancreatic
cancer53 and it has been shown that mir-142 highly expressed in mouse
hematopoietic tissues was found to be linked to an aggressive B-cell
leukemia.54 The human herpesvirus 8 (HHV-8) is associated with
both Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL).55
The Casey group reported that an editing event occurring on human
herpesvirus 8 Kaposin transcript (K12) can alter at the same time
both the kaposin A protein (changing serine 38 to glycine) and the
sequence of miR-K10 (at position 2 important for the target mRNA).
The authors showed that this editing event is essential for tumour
inhibition in a mouse model.56 It would be of interest to study editing
of miRNAs involved in cancers considering that they also represent
attractive molecules for exploitation as future therapeutic targets.
The authors are really grateful to Brendan Doe for helpful
comments and critical suggestions.
This work was supported by AIRC (Associazione Italiana per la
Ricerca sul Cancro) to A.G.
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