MAGOH and MAGOHB expression characterization and knockdown consequences

The exon junction complex (EJC) plays key roles throughout RNA life. Mutations or alterations in the expression levels of its components affect the nervous system in particular and, have been linked to microcephaly and neurological disorders. We investigated the involvement of two EJC members, the paralogs, MAGOH and MAGOHB, in brain tumor development. High MAGOH/MAGOHB expression was observed in 14 tumor types with glioblastoma (GBM) showing the highest difference in tumor vs. normal comparisons. Analysis of three distinct cohorts indicated that increased MAGOH/MAGOHB expression is associated with poor prognosis in glioma patients. MAGOH and MAGOHB knockdown in glioblastoma cells affected different cancer phenotypes, while astrocytes did not show any noticeable changes. Reduced MAGOH and MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulate fewer complexes on average in comparison to other exons in the same transcripts, providing a possible explanation for their sensitivity to MAGOH/ MAGOHB knockdown. Transcripts (genes) showing alterations in splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH and MAGOHB levels are required in two scenarios involving proliferating cells, brain development and GBM growth. MAGOH and MAGOHB high expression would safeguard the splicing of genes in high demand, ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not demand increased MAGOH and MAGOHB expression, MAGOH/MAGOHB targeting emerges as a therapeutic option to treat GBM.