RNA editing mediates the functional switch of COPA in a novel mechanism of hepatocarcinogenesis

Song, Yangyang; An, Ömer; Ren, Xi; Chan, Tim; Tay, Daryl Jin Tai; Tang, Sze Jing; Han, Jian; Hong, HuiQi; Ng, Vanessa Hui En; Ke, Xin-Yu; Shen, Haoqing; Pitcheshwar, Priyankaa; Lin, Jaymie Siqi; Leong, Ka Wai; Molias, Fernando Bellido; Yang, Henry; Kappei, Dennis; Chen, Leilei

doi:10.1016/j.jhep.2020.07.021

“…Next, COPA (coatomer subunit α) and COG3 (Component Of Oligomeric Golgi Complex 3), two reported protein-recoding editing targets regulated by ADAR2 42,43 , were chosen to study whether restoration of expression of the edited protein variant (COPA I164V or COG3 I635V ) could at least partially phenocopy ADAR2-mediated suppression of leukemogenesis of t(8;21) AML. We first confirmed that upon overexpression of the wildtype ADAR2 but not the DeAD or EAA mutant, the editing frequencies of editing sites in COPA and COG3 transcripts were dramatically increased in Kasumi-1 cells ( Supplemental Figure 2A, 2B ), indicating COPA and COG3 are indeed ADAR2 targets in t(8;21) AML cells.…”

Section: Resultsmentioning

confidence: 99%

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

Guo

¹

,

Chan

²

,

An

³

et al. 2021

Preprint

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In the past decade, adenosine to inosine (A-to-I) RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes ADAR1 and ADAR2, has been shown to contribute to the development and progression of multiple cancers; however, very little is known about its role in acute myeloid leukemia (AML) - the second most common type of leukemia making up 31% of all adult leukemia cases. Here, we found that ADAR2, but not ADAR1 and ADAR3, is specifically downregulated in core binding factor (CBF) AML with t(8;21) or inv(16). In t(8;21) AML, RUNX1-driven transcription of ADAR2 transcripts was found to be repressed by the RUNX1-ETO fusion protein. Forced overexpression of two ADAR2-regulated RNA editing targets COPA and COG3 indeed inhibits clonogenic growth of human t(8;21) AML cells. Further in vivo animal studies confirmed that ADAR2 could suppress leukemogenesis of t(8;21) AML through its RNA binding and editing capabilities. Our results suggest a novel RNA editing-mediated mechanism leading to t(8,12) AML.

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“…As shown in Figure 1B , editing in mRNA may results in missense mutations and alterations in the beginning and terminating translation ( 102 ). Multiple editing sites located in certain coding regions, such as AZIN1 ( 103 , 104 ), GABRA3 ( 105 , 106 ), and COPA ( 40 , 107 , 108 ), have been shown to affect tumor progression. According to the reported databases, most editing sites reside within non-coding regions (>90%), and RNA editing has been detected in many types of ncRNAs, including piRNAs ( 109 ).…”

Section: The Effects Of Adars Induced A-to-i Rna Editing In Cancermentioning

confidence: 99%

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

Wang

¹

,

Chen

²

,

Wei

³

et al. 2021

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As an important regulatory mechanism at the posttranscriptional level in metazoans, adenosine deaminase acting on RNA (ADAR)-induced A-to-I RNA editing modification of double-stranded RNA has been widely detected and reported. Editing may lead to non-synonymous amino acid mutations, RNA secondary structure alterations, pre-mRNA processing changes, and microRNA-mRNA redirection, thereby affecting multiple cellular processes and functions. In recent years, researchers have successfully developed several bioinformatics software tools and pipelines to identify RNA editing sites. However, there are still no widely accepted editing site standards due to the variety of parallel optimization and RNA high-seq protocols and programs. It is also challenging to identify RNA editing by normal protocols in tumor samples due to the high DNA mutation rate. Numerous RNA editing sites have been reported to be located in non-coding regions and can affect the biosynthesis of ncRNAs, including miRNAs and circular RNAs. Predicting the function of RNA editing sites located in non-coding regions and ncRNAs is significantly difficult. In this review, we aim to provide a better understanding of bioinformatics strategies for human cancer A-to-I RNA editing identification and briefly discuss recent advances in related areas, such as the oncogenic and tumor suppressive effects of RNA editing.

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“…Downregulation of COPB2 could inhibit the growth of human cholangiocellular carcinoma cells [32]. It has also been reported that reduced editing of COPA, an important paralog of COPB2, has been implicated in the pathogenesis of HCC, and editing of COPA WT may switch it from a tumor-promoting gene to a tumor suppressor by deactivating the PI3K/AKT/mTOR pathway through downregulation of caveolin-1 (CAV1) [20]. These findings suggest an essential role of COPB2 in the occurrence and progression of tumors, which provides a good theoretical basis for our study of the role of COPB2 in HCC.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, coatomer protein complex subunit alpha (COPA), another subunit of COPI, is an important paralog of COPB2 [18] and has been reported to be upregulated in tumors relative to paired adjacent nonmalignant tissues in patients with liver cancer [19]. It was also reported that reduced editing of COPA was implicated in the pathogenesis of HCC and editing of COPA WT may switch it from a tumorpromoting gene to a tumor suppressor by deactivating the PI3K/AKT/mTOR pathway through downregulation of caveolin-1 (CAV1) [20]. Deregulated mTOR signaling significantly contributes to the molecular pathogenesis of HCC [21].…”

Section: Introductionmentioning

confidence: 99%

COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC

Zhang

¹

,

Wang

²

,

Li

³

et al. 2021

BioMed Research International

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Purpose. This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). Methods. HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan–Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. Results. COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio OR = 1.616 , >20 vs. ≤20, p < 0.05 ), stage ( OR = 1.744 , III vs. I, p < 0.05 ), and grade ( OR = 1.746 , G4+G3 vs. G2+G1, p < 0.05 ). Kaplan–Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression ( p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio HR = 1.068 , p < 0.0001 ) and multivariate Cox ( HR = 2.011 , p < 0.05 ) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. Conclusion. COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.

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RNA editing mediates the functional switch of COPA in a novel mechanism of hepatocarcinogenesis

Cited by 42 publications

References 36 publications

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

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

COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC

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