A novel NFIA-NF?B feed-forward loop contributes to glioblastoma cell survival.

ABSTRACT:

Background

The nuclear factor I-A (NFIA) transcription factor promotes glioma growth and inhibits apoptosis in glioblastoma (GBM) cells. Here we report that the NFIA pro-survival effect in GBM is mediated in part via a novel NFIA-nuclear factor-kappaB (NF?B) p65 feed-forward loop.

Methods

We examined effects of gain- and loss-of-function manipulations of NFIA and NF?B p65 on each other's transcription, cell growth, apoptosis and sensitivity to chemotherapy in patient-derived GBM cells and established GBM cell lines.

Results

NFIA enhanced apoptosis evasion by activating NF?B p65 and its downstream anti-apoptotic factors tumor necrosis factor receptor-associated factor 1 (TRAF1) and cellular inhibitor of apoptosis proteins (cIAPs). Induction of NF?B by NFIA was required to protect cells from apoptosis, and inhibition of NF?B effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NF?B and anti-apoptotic genes TRAF1 and cIAPs, and increased baseline apoptosis. NFIA positively regulated NF?B transcription and NF?B protein level. Interestingly, NF?B also activated the NFIA promoter and increased NFIA level, and knockdown of NFIA was sufficient to attenuate the NF?B pro-survival effect, suggesting a reciprocal regulation between NFIA and NF?B in governing GBM cell survival. Supporting this, NFIA and NF?B expression levels were highly correlated in human GBM and patient-derived GBM cells.

Conclusions

These data define a previously unknown NFIA-NF?B feed-forward regulation that may contribute to GBM cell survival.

SUBMITTER: Lee J 

PROVIDER: S-EPMC5473440 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature