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 SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2 and CD44. Loss of SLFN11 stimulated expression of NF-kB target genes, consistent with a negative regulatory role for SLFN11 on the NF-kB pathway. Further, our studies identify p21 as a direct transcriptional target of NF-kB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 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.

Schlafens: Emerging Therapeutic Targets

“…Our group demonstrated in GBM that SLFN11 suppresses noncanonical NFκB signaling allowing for GBM progression [42]. We also demonstrated an association between SLFN11 and NFκB2, resulting in repression of the cell cycle blocker p21 [42].…”

“…Our group demonstrated in GBM that SLFN11 suppresses noncanonical NFκB signaling allowing for GBM progression [42]. We also demonstrated an association between SLFN11 and NFκB2, resulting in repression of the cell cycle blocker p21 [42]. Loss of SLFN11 stimulated NFκB2 dependent expression of p21, blocking GBM growth as demonstrated by increased survival of orthotopic PDXs lacking SLFN11.…”

“…Loss of SLFN11 stimulated NFκB2 dependent expression of p21, blocking GBM growth as demonstrated by increased survival of orthotopic PDXs lacking SLFN11. Additionally, GBM patients who have high SLFN11 levels exhibit worse overall survival [42]. Recently, SLFN11 has been linked to the malignant phenotype of clear cell renal cell carcinoma (ccRCC) promoting tumor growth, migration, and invasion [43].…”

Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy

“…On one hand, its upregulation in response to DNA damage caused by CRISPR/Cas9 may induce cell cycle arrest, preventing cells from proliferating and potentially compromising the effectiveness of the editing process [ 100 ]. On the other hand, P21 can promote DNA repair, which might be beneficial for repairing non-specific site effects [ 101 ]. Hence, understanding the interplay between P21 and CRISPR/Cas9 is essential for optimizing the editing outcomes [ 100 ].…”

“…Additionally, the activation of P21 may also facilitate DNA repair mechanisms, enhancing the cell's ability to detect and repair chemotherapy-induced DNA damage, thus reducing the chance of drug resistance. Dysregulation of P53 or P21 in CRISPR/Cas9 genome editing could lead to several outcomes [ 101 ]. Excessive activation of P53 might trigger cell death pathways, resulting in increased toxicity and adverse effects [ 100 ].…”