A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer

Nakano, Masataka; Fukami, Tatsuki; Gotoh, Saki; Nakajima, Miki

doi:10.1074/jbc.m117.775684

Cited by 99 publications

(93 citation statements)

References 75 publications

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“…Interestingly, the increase in ADAR1 occurs at both RNA and protein levels, suggesting that the regulation happens at the transcriptional level. A recent study has shown that an increase in ADAR1mediated editing of DHFR, a key molecule that is involved in tumour resistance to methotrexate, leads to an increase in its expression in the BC cell line MCF-7 [39]. Furthermore, in our study, both ADAR1 and nuclear factor 90 (NF90) mRNA levels were found to be elevated in all BC subtypes, particularly in basal-like BC (Fig.…”

Section: Adar1 Expression Is Elevated In Specific Bc Subtypes and Stagessupporting

confidence: 70%

“…Elevated RNA editing in cancers also correlates with poor survival rates [38]. ADAR1 also regulates gene expression in BC cells [39]. All these studies support the argument that deregulation of ADARs or their activity could contribute to BC progression.…”

Section: Adar1 Expression Is Elevated In Specific Bc Subtypes and Stagesmentioning

confidence: 72%

“…In another study, Nakano et al . , identified 26 RNA editing sites within the 3′UTR of dihydrofolate reductase (DHFR) (a key molecule involved in tumour resistance to methotrexate). Here, the authors demonstrated that ADAR1 enhanced DHFR expression by editing the miR‐25‐3p‐ and miR‐125a‐3p‐binding sites within the 3′‐UTR of DHFR , thereby negatively regulating miRNA‐mediated gene repression .…”

Section: Resultsmentioning

confidence: 99%

“…A recent study has reported that the A-to-I editing frequency is increased in BC cells, compared to normal cells, primarily due to the increased ADAR levels in BC cells [35]. In another study, Nakano et al [39], identified 26 RNA editing sites within the 3 0 UTR of dihydrofolate reductase (DHFR) (a key molecule involved in tumour resistance to methotrexate). Here, the authors demonstrated that ADAR1 enhanced DHFR expression by editing the miR-25-3p-and miR-125a-3p-binding sites within the 3 0 -UTR of DHFR, thereby negatively regulating miRNA-mediated gene repression [39].…”

Section: Adar1 Levels Are Elevated In Bc Subtypesmentioning

confidence: 99%

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RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

et al. 2017

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Adenosine Deaminases acting on RNA (ADARs) are proteins that catalyze widespread A-to-I editing within RNA sequences. We recently reported that ADAR2 edits and stabilizes nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA). Here, we report that ADAR1 coordinates with ADAR2 to regulate editing and stability of Ctn RNA. We observe an RNA-dependent interaction between ADAR1 and ADAR2. Furthermore, ADAR1 negatively regulates interaction of Ctn RNA with RNA-destabilizing proteins. We also show that breast cancer (BC) cells display elevated ADAR1 but not ADAR2 levels, compared to non-tumorigenic cells. Additionally, BC patients with elevated levels of ADAR1 show low survival. Our findings provide insights into overlapping substrate preferences of ADARs and potential involvement of ADAR1 in breast cancer.

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Section: Adar1 Expression Is Elevated In Specific Bc Subtypes and Stagessupporting

confidence: 70%

Section: Adar1 Expression Is Elevated In Specific Bc Subtypes and Stagesmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Adar1 Levels Are Elevated In Bc Subtypesmentioning

confidence: 99%

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RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

et al. 2017

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“…A-to-I RNA editing at codon 72 (Asn→Asp) of SLC22A3 may serve as an additional epigenetic mechanism relevant to esophageal cancer susceptibility. A link between A-to-I RNA editing and cancer has been established in the past few years (33)(34)(35)(36)(37)(38). Until now, only a few proteins with amino acid substitutions that are caused by a single site-specific RNA-editing event have been reported with validity, and there is no apparent causal relationship between altered RNA-editing levels and the initiation of cancer progression.…”

Section: Discussionmentioning

confidence: 99%

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer

Qin

Ming

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genomewide association study, is positively correlated with the editing level of SLC22A3. Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.RNA editing | metastasis suppressor | familial ESCC | SLC22A3 | ADAR2

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Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

Hariharan

Rehrauer

et al. 2022

Molecular Oncology

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We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

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A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer

Cited by 99 publications

References 75 publications

RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer

Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

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