Abstract 1932: The importance of RNA editing enzymes in glioblastoma

Abstract

Abstract This study was supported by AIRC. Glioblastoma (or grade IV astrocytomas) is a highly heterogeneous and deadly malignant brain tumor and one of the most incurable form of cancer in human that urgently needs new therapeutic targets. There is great interest in elucidating all the molecular basis and functional importance of genetics and epigenetic mechanisms occurring in glioblastoma. In our laboratory, we investigate whether essential post-transcriptional event (such as the A-to-I RNA editing) is a possible molecular mechanism involved in the appearance/progression of glioblastoma. A-to-I RNA editing modifies the nucleotide sequence of RNA target molecules. The ADARs (Adenosine Deaminases that Act on RNA) are the enzymes responsible for this conversion acting on pre-mRNAs or non-coding RNAs (such as microRNA). Inosine, is recognized by the translation and splicing machineries, as Guanosine. Therefore, ADARs can play a direct and critical role in generating alternative protein isoforms (by codon changes and splicing pattern alterations) and modulating gene expression levels (by editing microRNAs and/or 3’-UTRs). In mammals, there are three different ADAR enzymes (ADAR1-3). The deregulation of ADAR2 activity has been connected with several neurological human diseases and Adar2 knockout animals show a lethal neurological phenotype. We demonstrated a direct correlation between a progressive decrease of ADAR2 editing activity and the increased grade of malignancy in paediatric astrocytomas (from grade I to grade IV). We show that the rescue of ADAR2 in glioblastoma cells is able to significantly inhibit in vivo glioblastoma tumor growth. Differently, when we decrease the expression of ADAR2 in malignant but not tumorigenic astrocytoma cell line (A172) we observed a boost of several cancers cell features such as cell proliferation, migration and colony formation. By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we observed that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells that may contribute to cancer progression. Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better dissect the impact of ADAR2 editing enzyme in glioblastoma. Citation Format: Angela Gallo. The importance of RNA editing enzymes in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1932.