Abstract A24: Contribution of aberrant splicing mechanisms in glioblastoma development

Abstract According to the World Health Organization, glioblastoma multiforme (GBM) represents 15-20% of all primary intracranial tumors and it is one of the most worrisome types of tumor, due to its high aggressiveness with low response to treatments. Currently, most patients diagnosed with GBM survive less than 15 months after diagnosis. Thus, there is a growing interest in the study of molecular signatures that contribute to a more effective therapy. Given the high prevalence of defects in splicing mechanisms found in cancer, small modulating splicing molecules have been presented as novel therapeutic strategies for the treatment of this malignant disease. In addition, alternative splicing appears to be more active in the nervous system compared to that detected in other tissues. In the last decade, some studies have reinforced the hypothesis that aberrant alternative splicing of RNA contributes to tumorigenesis, especially in GBM, and that changes in splicing mechanism of some genes could redirect this process. RNA binding proteins (RBPs) are the main regulators of alternative splicing mechanisms and thus could contribute to the acquisition of the malignant phenotype. A recent study from our group, focused exclusively in GBM, has shown several RBPs with deregulated expression on GBM compared to normal tissue (Correa et al., 2016). Among them, the MAGOH, an EJC complex component that plays a key role in mRNA metabolism, seems to participate on splicing regulation and has been implicated as possible oncogenic factor. Furthermore, the previous study from our group has also showed that MAGOH significantly increased the survival and proliferation of glioblastoma cell lines. Knowing that splicing machinery is a tangible target, we believe it is a possible new therapeutic route for GBM treatment. Thus, due to MAGOH participation in splicing regulation and on acquisition of GBM malignant phenotype, we have proposed to characterize, for the first time, new regulatory routes of gliomagenesis by a global analysis of MAGOH effects on alternative splicing pathways in GBM. By global analysis of public data, we identified aberrantly expressed genes on GBM compared to normal brain tissue. In addition, after MAGOH knockdown, we have identified some aberrantly expressed genes and also altered splicing events in glioblastoma cells compared to wild type. Together, the results corroborate our hypothesis that MAGOH contributes to glioma cells' malignant transformation with controlling splicing mechanism and interfering on gene expression. Citation Format: Fabiana Marcelino Meliso, Luis Penalva, Pedro Alexandre Favoretto Galante. Contribution of aberrant splicing mechanisms in glioblastoma development [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A24.