A TRANSLATIONAL REPRESSION PROGRAM IS ASSOCIATED WITH THE STEM CELL STATE IN GLIOBLASTOMA

Glioblastoma is the most prevalent and lethal brain tumor. Within glioblastoma, stem-like glioma stem cells (GSCs) contribute to the heterogeneous and highly aggressive nature of the tumor. It is critical to decipher the changes in the regulation of gene expression that accompany the differentiation from GSCs to differentiated glioma cells (DGCs). To date, such changes have only been investigated on the transcriptional and proteomic levels but not on the translational level, despite the key role that the regulation of protein production plays in all aspects of cellular function. Here, we interrogated changes in the translational landscape during the differentiation of patient-derived GSCs into DGCs. We utilized ribosome profiling to assess translation on a transcriptome wide level in both GSCs and DGCs. We identified a translational repression program in GSCs wherein a significant subset of transcripts (>1,600) is translationally repressed. Roughly 80% of these transcripts are de-repressed upon differentiation in DGCs, including genes with roles in Wnt-signaling and ribosome structure and function. Most notably, we find that the poly(A) binding protein interacting protein 2B (PAIP2B) is most preferentially translated gene in GSCs when compared to DGCs. PAIP2B is a broad yet transcript-specific repressor of translation that antagonizes poly(A) binding proteins (PABPs), which are broad activators of translation. Interestingly, PABPs are preferentially translated in DGCs. Our results suggest that glioblastoma cells utilize the PAIP2B-PABP axis to exert translational control over the transcriptome in order to maintain the cancer stem cell state and to drive the differentiation of GSCs.