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

作者：Lee JunSung; Hoxha Edlira; Song Hae Ri^*

来源：Neuro-Oncology, 2017, 19(4): 524-534.

DOI：10.1093/neuonc/now233

• apoptosis
• chemoresistance
• glioblastoma (GBM)
• NF kappa B
• nuclear factor I-A (NFIA)

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 kappa B) p65 feed-forward loop.
Methods. We examined effects of gain-and loss-of-function manipulations of NFIA and NF kappa 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 kappa 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 kappa B by NFIA was required to protect cells from apoptosis, and inhibition of NF kappa B effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NF kappa B and anti-apoptotic genes TRAF1 and cIAPs, and increased baseline apoptosis. NFIA positively regulated NF kappa B transcription and NF kappa B protein level. Interestingly, NF kappa B also activated the NFIA promoter and increased NFIA level, and knockdown of NFIA was sufficient to attenuate the NF kappa B pro-survival effect, suggesting a reciprocal regulation between NFIA and NF kappa B in governing GBM cell survival. Supporting this, NFIA and NF kappa B expression levels were highly correlated in human GBM and patient-derived GBM cells.
Conclusions. These data define a previously unknown NFIA-NF kappa B feed-forward regulation that may contribute to GBM cell survival.

• 出版日期2017-4