CBIO-39DOWN-REGULATION OF NFIA SENSITIZES GLIOMA TO CHEMOTHERAPY-INDUCED APOPTOSIS

Abstract

The Nuclear Factor I-A (NFIA) transcription factor was recently identified as a glioma tumor promoter. We previously reported that NFIA inhibits chemotherapy-induced apoptosis glioblastoma (GBM) cells. However, the mechanism by which the NFIA regulates cell survival and drug resistance is not fully understood. We now report that NFIA enhances apoptosis evasion through activating the NFkB p65 and its downstream anti-apoptotic factors (TRAF1 and cIAPs). Induction of NFkB by NFIA is required to protect cells from apoptosis, and inhibition of NFkB (siRNA or inhibitors) effectively reversed NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased NFkB and anti-apoptotic gene expression and ultimately induced apoptosis. Mechanistic investigation demonstrated that NFIA positively regulates NFkB transcription and protein level. Interestingly we also found that NFkB activates the NFIA promoter and increases NFIA level and that knockdown of NFIA is sufficient to attenuate NFkB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFkB. Consistent with our findings, NFIA and NFkB levels and expression are highly associated in human primary GBM and patient-derived GBM cells. Collectively, these data define previously unknown NFIA-NFkB feed-forward regulation that controls GBM cell survival and drug resistance.