A-to-I RNA Editing in Cancer: From Evaluating the Editing Level to Exploring the Editing Effects

Wang, Heming; Chen, Sinuo; Wei, Jiayi; Song, Guangqi; Zhao, Yicheng

doi:10.3389/fonc.2020.632187

Cited by 23 publications

(14 citation statements)

References 152 publications

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“…Among all allelic change features, “A>G,” “C>A,” “C>G,” and “G>A” were retained. Out of which, “A>G” and “G>A” represented A-to-I ( Wang et al, 2021 ) and C-to-U ( Lerner et al, 2019 ) RNA editing events, and their existence had negative impacts on the model output. On the contrary, “C>A” and “C>G” represented RNA-editing exclusive allelic changes that exhibited positive impacts.…”

Section: Resultsmentioning

confidence: 99%

RNA-SSNV: A Reliable Somatic Single Nucleotide Variant Identification Framework for Bulk RNA-Seq Data

Long

Yuan

2022

Front. Genet.

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The usage of expressed somatic mutations may have a unique advantage in identifying active cancer driver mutations. However, accurately calling mutations from RNA-seq data is difficult due to confounding factors such as RNA-editing, reverse transcription, and gap alignment. In the present study, we proposed a framework (named RNA-SSNV, https://github.com/pmglab/RNA-SSNV) to call somatic single nucleotide variants (SSNV) from tumor bulk RNA-seq data. Based on a comprehensive multi-filtering strategy and a machine-learning classification model trained with comprehensively curated features, RNA-SSNV achieved the best precision–recall rate (0.880–0.884) in a testing dataset and robustly retained 0.94 AUC for the precision–recall curve in three validation adult-based TCGA (The Cancer Genome Atlas) datasets. We further showed that the somatic mutations called by RNA-SSNV tended to have a higher functional impact and therapeutic power in known driver genes. Furthermore, VAF (variant allele fraction) analysis revealed that subclonal harboring expressed mutations had evolutional selection advantage and RNA had higher detection power to rescue DNA-omitted mutations. In sum, RNA-SSNV will be a useful approach to accurately call expressed somatic mutations for a more insightful analysis of cancer drive genes and carcinogenic mechanisms.

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Section: Resultsmentioning

confidence: 99%

RNA-SSNV: A Reliable Somatic Single Nucleotide Variant Identification Framework for Bulk RNA-Seq Data

Long

Yuan

2022

Front. Genet.

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“…Nm, also called 2′-O-methylation, is the methylation of the 2′ -hydroxyl of ribonucleotides, which is a highly conserved RNA modification in eukaryotes [ 21 ], and it was determined to affect the tumorigenesis of colorectal cancer by regulating rRNA [ 22 ]. Ψ is the transition from uridine to pseudouridine [ 23 ], and A-to-I is the conversion from adenine to inosine [ 24 ]. M 1 A is the methylation of adenosine at position 1, m 7 G is the methylation of guanosine at position 7 [ 25 ], and mcm 5 s 2 U is an important post-transcriptional modification of U34 on specific tRNAs [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk of Eight Types of RNA Modification Regulators Defines Tumor Microenvironments, Cancer Hallmarks, and Prognosis of Lung Adenocarcinoma

Mao

Chen

et al. 2022

Journal of Oncology

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RNA modification has become an exciting underexplored field in recent years. In lung adenocarcinoma (LUAD), m6A was the best characterized and most studied RNA modification, while knowledge about other kinds of RNA modifications in LUAD is limited. In our study, we included a total of 100 RNA modification regulators of eight types of cancer-related RNA modifications (m6A, m1A, m5C, Nm, m7G, Ψ, A-to-I, and mcm5s2U) to systematically profile their specific roles in LUAD. By gene mutation and expression analysis, we identified extensive dysregulations and complicated interactions of 100 RNA modification regulators in LUAD. Based on unsupervised clustering analysis, gene set variation analysis (GSVA), and single-sample gene-set enrichment analysis (ssGSEA), two RNA modification patterns in LUAD were defined to show distinct biological characteristics. The favorable prognostic pattern was enriched with infiltrated immune cells, including activated B cells, CD8 T cells, eosinophil cells, dendritic cells, and natural killer cells, while the unfavorable prognostic pattern was enriched with cancer hallmarks, including hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, PI3K-AKT-mTOR pathway, MYC pathway, and glycolysis pathway. We also constructed an RNA modification score (RMScore) based on five critical genes (CYP17A1, NTSR1, PITX3, KRT6A, and ANLN) to evaluate the RNA modification status of individual LUAD patients. RMScore was revealed to be related to the infiltrated immune cells and cancer hallmarks and was an independent prognostic factor in the TCGA-LUAD cohort and two external GEO-LUAD cohorts. Our study was the first to comprehensively investigate the dysregulations, crosstalk, and potential prognostic value of eight types of RNA modifications in LUAD. Our results highlighted the significance of eight types of RNA modifications in tumor microenvironments and cancer hallmarks and provided novel prognostic biomarkers and potential therapeutic targets in the management of LUAD patients in the future.

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“…Therefore, identifying novel and e cacious drug targets is urgently needed to expand therapeutic options for lethal PCa. ADAR1-mediated deamination of adenosine-to-inosine (A-to-I) within double-stranded RNA (dsRNA) is the most prevalent form of RNA editing that modi es the sequence of RNA transcripts without changing its genomic blueprints, and its aberration has revealed a close association with autoimmune disease Aicardi-Goutieres Syndrome (AGS), neurodegenerative disease Autism and many kinds of cancer (14,54). Although previous study has reported that PCA3/PRUNE2 axis is mediated by ADAR1 dependent RNA editing effects on tumor growth in AR-dependent prostate cancer cell lines (33), little is known about the role of ADAR1 in AR-negative prostate cancer, and the landscape of A-to-G editing targets in PCa remains underexplored.…”

Section: Discussionmentioning

confidence: 99%

Targeting ADAR1 with a Novel Small-Molecule for the Treatment of Prostate Cancer

Xiao

Zhu

et al. 2021

Preprint

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Despite initial response to androgen signaling therapy, most prostate cancer (PCa) patients eventually relapse and remain incurable. ADAR1-mediated A-to-G editing plays oncogenic roles in various tumors. However, the specific function of ADAR1 and the global RNA edited targets governing PCa progression remain underexplored. Here, we demonstrate that highly expressed ADAR1 as a crucial oncogenic target in PCa, and develop a novel small-molecule ADAR1 inhibitor ZYS-1 with significant anti-tumor efficacy and favorable safety profile. Either depletion or pharmacological inhibition of ADAR1 dramatically suppress PCa growth, inhibit metastasis, and potentiate immune response. We further reveal that the translation of MTDH is repressed by ADAR1 in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, these results shed light on ADAR1 as a novel druggable target in PCa therapy and highlight the widespread applicability of ADAR1 inhibitors for a broad spectrum of malignancies.

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A-to-I RNA Editing in Cancer: From Evaluating the Editing Level to Exploring the Editing Effects

Cited by 23 publications

References 152 publications

RNA-SSNV: A Reliable Somatic Single Nucleotide Variant Identification Framework for Bulk RNA-Seq Data

RNA-SSNV: A Reliable Somatic Single Nucleotide Variant Identification Framework for Bulk RNA-Seq Data

Crosstalk of Eight Types of RNA Modification Regulators Defines Tumor Microenvironments, Cancer Hallmarks, and Prognosis of Lung Adenocarcinoma

Targeting ADAR1 with a Novel Small-Molecule for the Treatment of Prostate Cancer

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