A novel tumor-promoting role for nuclear factor IA in glioblastomas is mediated through negative regulation of p53, p21, and PAI1

Jun Sung Lee, Jiping Xiao, Parita Patel, Jake Schade, Jinhua Wang, Benjamin Deneen, Anat Erdreich-Epstein, Hae Ri Song

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

BackgroundNuclear factor IA (NFIA), a transcription factor and essential regulator in embryonic glial development, is highly expressed in human glioblastoma (GBM) compared with normal brain, but its contribution to GBM and cancer pathogenesis is unknown. Here we demonstrate a novel role for NFIA in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions.MethodsTo determine the role of NFIA in glioma, we examined the effects of NFIA in growth, proliferation, apoptosis, and migration. We used gain-of-function (overexpression) and loss-of-function (shRNA knockdown) of NFIA in primary patient-derived GBM cells and established glioma cell lines in culture and in intracranial xenografts in mouse brains.ResultsKnockdown of native NFIA blocked tumor growth and induced cell death and apoptosis. Complementing this, NFIA overexpression accelerated growth, proliferation, and migration of GBM in cell culture and in mouse brains. These NFIA tumor-promoting effects were mediated via transcriptional repression of p53, p21, and plasminogen activator inhibitor 1 (PAI1) through specific NFIA-recognition sequences in their promoters. Importantly, the effects of NFIA on proliferation and apoptosis were independent of TP53 mutation status, a finding especially relevant for GBM, in which TP53 is frequently mutated.ConclusionNFIA is a modulator of GBM growth and migration, and functions by distinct regulation of critical oncogenic pathways that govern the malignant behavior of GBM.

Original languageEnglish (US)
Pages (from-to)191-203
Number of pages13
JournalNeuro-Oncology
Volume16
Issue number2
DOIs
StatePublished - Jan 2014

Keywords

  • PAI1
  • glioblastoma (GBM)
  • glioma
  • nuclear factor IA (NFIA)
  • p21
  • p53

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