title: A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival.
abstract: 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 (NFκB) p65 feed-forward loop.
  
  
  
  We examined effects of gain- and loss-of-function manipulations of NFIA and NFκB p65 on each other's transcription, cell growth, apoptosis and sensitivity to chemotherapy in patient-derived GBM cells and established GBM cell lines.
  
  
  
  NFIA enhanced apoptosis evasion by activating NFκB p65 and its downstream anti-apoptotic factors tumor necrosis factor receptor-associated factor 1 (TRAF1) and cellular inhibitor of apoptosis proteins (cIAPs). Induction of NFκB by NFIA was required to protect cells from apoptosis, and inhibition of NFκB effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NFκB and anti-apoptotic genes TRAF1 and cIAPs, and increased baseline apoptosis. NFIA positively regulated NFκB transcription and NFκB protein level. Interestingly, NFκB also activated the NFIA promoter and increased NFIA level, and knockdown of NFIA was sufficient to attenuate the NFκB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFκB in governing GBM cell survival. Supporting this, NFIA and NFκB expression levels were highly correlated in human GBM and patient-derived GBM cells.
  
  
  
  These data define a previously unknown NFIA-NFκB feed-forward regulation that may contribute to GBM cell survival.
authors.affiliation: Department of Neurosurgery, New York University, School of Medicine, New York, NY, USA.
authors.forename: JunSung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, New York University, School of Medicine, New York, NY, USA.
authors.forename: Edlira
authors.initials: E
authors.lastname: Hoxha
authors.affiliation: Department of Neurosurgery, New York University, School of Medicine, New York, NY, USA.|Department of Neurology, New York University, School of Medicine, New York, NY, USA.|Brain Tumor Center, Perlmutter Cancer Center, New York University, School of Medicine, New York, NY, USA.
authors.forename: Hae-Ri
authors.initials: HR
authors.lastname: Song
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D051839:NFI Transcription Factors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051839:NFI Transcription Factors; C497592:NFIA protein, human; D051996:Transcription Factor RelA
keywords: NFκB; apoptosis; chemoresistance; glioblastoma (GBM); nuclear factor I-A (NFIA)