SLFN11 Negatively Regulates Noncanonical NFκB Signaling to Promote Glioblastoma Progression

Abstract

Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular and tumor biology of GBM. CRISPR/Cas9 mediated knockout (KO) of <i>SLFN11</i> inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as <i>NES</i>, <i>SOX2</i> and <i>CD44</i>. Loss of <i>SLFN11</i> stimulated expression of NF-κB target genes, consistent with a negative regulatory role for SLFN11 on the NF-κB pathway. Further, our studies identify p21 as a direct transcriptional target of NF-κB2 in GBM whose expression was stimulated by loss of <i>SLFN11</i>. Genetic disruption of <i>SLFN11</i> blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.