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Survival factor NFIL3 restricts FOXO-induced gene expression in cancer

Megan Keniry1, Maira M Pires, Sarah Mense

  • 1Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.

Genes & Development
|May 1, 2013
PubMed

Insights

Nuclear factor interleukin 3-regulated (NFIL3) represses FOXO transcription factors, impacting cancer cell survival and death. Targeting NFIL3 may offer therapeutic benefits for cancer patients by restoring FOXO-regulated gene expression.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • FOXO transcription factors regulate diverse cellular processes, including cell death and lifespan.
  • Understanding how FOXO factors select specific target genes is crucial for deciphering their varied functions.

Purpose of the Study:

  • To identify genes that modulate FOXO transcription factor activity, specifically focusing on the regulation of TRAIL (TNF-related apoptosis-inducing ligand).
  • To investigate the role of NFIL3 in FOXO-mediated gene regulation and its implications in cancer.

Main Methods:

  • A genetic screen was employed to identify modifiers of FOXO activation of the TRAIL promoter.
  • Chromatin immunoprecipitation and reporter assays were used to assess NFIL3 binding and its effect on histone acetylation.
  • Expression analysis of NFIL3 in various cancer types and correlation with patient survival.

Main Results:

  • NFIL3, a bZIP transcriptional repressor, was identified as an inhibitor of FOXO transcription factor access to the TRAIL promoter.
  • NFIL3 recruits histone deacetylase-2 (HDAC2), leading to reduced histone acetylation and repression of FOXO target genes like FAS and GADD45.
  • NFIL3 overexpression in cancers correlates with reduced patient survival and promotes tumor cell survival by repressing TRAIL and antagonizing cell death.

Conclusions:

  • NFIL3 functions as a critical regulator of FOXO-mediated gene expression by altering chromatin accessibility.
  • NFIL3's repression of specific FOXO targets, including TRAIL, contributes to cancer cell survival and poor prognosis.
  • Targeting NFIL3 presents a potential therapeutic strategy for enhancing cancer treatment efficacy.

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