Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A.

Asra Abukar,Manuel Ronner,Emanuela Felley-Bosco,Marika Sculco,Agata Okonska,Jelena Kresoja-Rakic,Suna Sun,Victor W Beusechem,Ananya Hariharan,Hubert Rehrauer,Weihong Qi,Martin Wipplinger

doi:10.3390/cells10123543

Abstract

Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its mRNA editing. RBM8A protein expression was higher in mesothelioma compared to mesothelial cells. Silencing RBM8A changed splicing patterns in mesothelial and mesothelioma cells but drastically reduced viability only in mesothelioma cells. In the tissues of asbestos-exposed mice, editing of Rbm8a mRNA was associated with increased protein immunoreactivity, with no change in mRNA levels. Increased adenosine deaminase acting on dsRNA (ADAR)-dependent editing of Alu elements in the RBM8A 3′UTR was observed in mesothelioma cells compared to mesothelial cells. Editing stabilized protein expression. The unedited RBM8A 3′UTR had a stronger interaction with Musashi (MSI) compared to the edited form. The silencing of MSI2 in mesothelioma or overexpression of Adar2 in mesothelial cells resulted in increased RBM8A protein levels. Therefore, ADAR-dependent editing contributes to maintaining elevated RBM8A protein levels in mesothelioma by counteracting MSI2-driven downregulation. A wider implication of this mechanism for the translational control of protein expression is suggested by the editing of similarly structured Alu elements in several other transcripts.

Highlights

Malignant mesothelioma is a rapidly fatal tumor arising in the mesothelium, which has mesodermal origins and covers many important internal organs, such as the lungs, peritoneal cavities, the sacs surrounding the heart, and the testis
These data indicate that the overexpression of Adar2 in mesothelial cells recapitulates a characteristic of RNA-binding motif protein 8a (RBM8A) observed in malignant pleural mesothelioma (MPM), namely, the increased editing of its 3′untranslated region (UTR) associated with increased protein levels
We show that RBM8A protein levels are higher in mesothelioma cells

Summary

Introduction

Malignant mesothelioma (reviewed in [1,2]) is a rapidly fatal tumor arising in the mesothelium, which has mesodermal origins and covers many important internal organs, such as the lungs (pleural mesothelioma), peritoneal cavities (peritoneal mesothelioma), the sacs surrounding the heart (pericardial mesothelioma), and the testis (tunica vaginalis mesothelioma). Exposure to asbestos has been clearly identified as a cause of mesothelioma, and the use of asbestos has been banned in several countries, there are several developing nations that continue to use it [1] This means that the incidence of mesothelioma will continue to rise in the years to come. RBM8A forms a heterodimer with MAGOH [4] as a part of the exon junction complex (EJC) core. The latter participates in several mechanisms involved in the post-transcriptional control of messenger RNA (mRNA) expression regulating the location, the amount, and the duration of protein expression. Recognition of 3 UTR sequences by RNA-binding proteins and miRNAs alters the 3 UTR ribonucleoprotein (RNP) composition and regulates mRNA localization, translation, and stability [5,6]. RBM8A silencing in MSTO-211H mesothelioma cells reduced cell viability and induced apoptosis [11], consistent with the analysis of the Dependency Map Project (https://depmap.org/portal/depmap/, accessed on 21 October 2020 [12,13]), which revealed that RBM8A silencing is synthetically lethal in most of the cancer cell lines

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