MSI1 promotes the expression of the GBM stem cell marker CD44 by impairing miRNA-dependent degradation. [RNA-Seq II]

The stem cell marker Musashi1 (MSI1) is highly expressed during neurogenesis and in Glioblastoma (GBM). In cancer and non-malignant progenitor cells, MSI1 promotes self-renewal and impairs differentiation, involving the regulation of mRNA translation. However, a comprehensive understanding of MSI1's role in promoting GBM-driving networks remains to be deciphered. Overall design: In this study we use GBM-derived in vitro models of pediatric and adult origin, including isolated primary tumorspheres, to characterize GBM-driving roles of MSI1. We demonstrate that MSI1 is highly expressed in GBM recurrences, a major defiance in terms of surgery and chemo-/radiotherapy. In adult as well as pediatric GBM cell models, MSI1 promotes stem cell-like characteristics, most prominently elevated self-renewal potential and de-differentiation. For the first time, we provide evidence that MSI1 promotes the expression of stem cell markers like CD44, co-expressed with MSI1 within the migrating cell front of primary GBM samples. In GBM cell models MSI1 impairs CD44 downregulation by miRNAs revealing a new function of MSI1 in promoting stem cell properties, the 3'UTR- and miRNA-dependent control of mRNA turnover. This regulation is impaired by the previously reported MSI1 inhibitor luteolin. In sum, our findings reveal a role of MSI1 in stabilizing stem cell marker-encoding mRNAs in GBM and provide further evidence for its therapeutic target potential in GBM treatment.