Data from SLFN11 Negatively Regulates Noncanonical NFκB Signaling to Promote Glioblastoma Progression

Abstract

<div><p>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 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 NFκB target genes, consistent with a negative regulatory role for SLFN11 on the NFκB pathway. Furthermore, our studies identify p21 as a direct transcriptional target of NFκB2 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.</p>Significance:<p>We identify a negative regulatory role for SLFN11 in noncanonical NFκB signaling that results in suppression of the cell-cycle inhibitor p21. We provide evidence that SLFN11 contributes to regulation of stem cell markers in GBM, promoting the malignant phenotype. In addition, SLFN11 targeting triggers p21 expression and antitumor responses. Our studies define a highly novel function for SLFN11 and identify it as a potential therapeutic target for GBM.</p></div>