CBIO-09. ONCOGENIC ROLE OF NFIA-NFκB IN GLIOMA

Abstract

The NFIA transcription factor is a glioma tumor promoter. The mechanism by which NFIA regulates glioma cell survival and drug resistance is unknown. Here we report that the NFIA pro-survival effect is mediated via an NFIA-NFκB p65 feedforward loop. We examined effects of gain- and loss-of-function manipulations of NFIA and NFκB p65 on cell growth, apoptosis and sensitivity to chemotherapy in patient-derived GBM cells. NFIA inhibited apoptosis by activation of NFkB p65 and its downstream anti-apoptotic factors. Induction of NFκB by NFIA was required for apoptosis evasion, and inhibition of NFκB effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NFκB and its downstream anti-apoptotic genes and increased baseline apoptosis. Using transcriptome- and genome-wide approach, we demonstrated that NFIA directly regulated NFκB transcription. In addition, we found that NFκB activated the NFIA transcription and that knockdown of NFIA was sufficient to attenuate the NFκB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFκB in governing GBM cell growth and survival. Supporting this, NFIA and NFκB expression levels were highly correlated in human GBMs and patient-derived GBM cells. Interestingly, we found that NFIA has splice isoforms in human GBM, which significantly promoted growth of GBM cells and malignant transformation of normal astrocytes. Furthermore, NFIA and the two active isoforms potently increased activity of NFκB p65 in GBM cells. These findings suggest that GBM-active NFIA isoforms differentially affect GBM initiation and progression in part by activating NFκB p65. Collectively, these data define a novel NFIA-NFκB feedforward regulation that promotes GBM tumorigenesis and malignant behavior.