Abstract
Simple SummaryGlioblastoma (GBM) is one of the most aggressive tumor types with no effective treatment options. To create new routes for therapy, it is necessary to continue mapping new pathways contributing to gliomagenesis. In this regard, there is growing evidence that RNA binding proteins (RBPs) are major contributors to expression alterations affecting genes in signaling pathways critical to GBM growth and response to therapy. We have established Musashi1 (Msi1) as a main player in GBM and medulloblastoma and as a marker of clinical outcome and response to therapy. Our genomic and functional analyses established that Msi1 directly and indirectly regulates the expression of a network of genes, promoting cell cycle progression and DNA replication. Ultimately, Msi1 impact on this network has important consequences in tumor initiation, growth and response to therapy.RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in their levels are often observed in tumors with numerous oncogenic RBPs identified in recent years. Musashi1 (Msi1) is an RBP and stem cell gene that controls the balance between self-renewal and differentiation. High Msi1 levels have been observed in multiple tumors including glioblastoma and are often associated with poor patient outcomes and tumor growth. A comprehensive genomic analysis identified a network of cell cycle/division and DNA replication genes and established these processes as Msi1’s core regulatory functions in glioblastoma. Msi1 controls this gene network via two mechanisms: direct interaction and indirect regulation mediated by the transcription factors E2F2 and E2F8. Moreover, glioblastoma lines with Msi1 knockout (KO) displayed increased sensitivity to cell cycle and DNA replication inhibitors. Our results suggest that a drug combination strategy (Msi1 + cell cycle/DNA replication inhibitors) could be a viable route to treat glioblastoma.
Highlights
Glioblastoma (GBM) is one of the most aggressive tumor types with no effective treatment options
Since Msi1 has been implicated in regulating cancer stem cells [5,12,26], we investigated its impact on glioma stem cells (GSCs)
In Msi1 KO glioblastoma cells, we observed that G1-S transition is disrupted, agreeing with an increase in expression of Msi1 targets p21 and p27 and downregulation of CDK2 and CCNE2. p21 and p27 accumulation inhibits the activity of the cyclin complexes and prevents the transition from G1 to S phase
Summary
Glioblastoma (GBM) is one of the most aggressive tumor types with no effective treatment options. In The Cancer Genome Atlas (TCGA), hundreds of GBM tumors were analyzed for DNA copy number, DNA methylation, and gene expression [1]. The results of these analyses largely increased our knowledge and helped improve GBM classification. To map new pathways contributing to GBM development and to potentially create new routes for therapy, we turned our attention to oncogenic RNA binding proteins (RBPs) and their network of targets. Over 1500 RBPs have been cataloged in the human genome [2] Changes in their levels or functional activity can lead to multiple alterations in RNA processing and expression that can eventually contribute to the acquisition of cancerrelevant phenotypes [3]. RBP inhibition supposedly could affect multiple oncogenic pathways at once, providing a robust alternative in cancer therapy [6]
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