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FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway

Kevin Kelley1, Steven J Berberich

  • 1Wright State University, Boonshoft School of Medicine, Biochemistry & Molecular Biology Department, 3640 Colonel Glenn Hwy, Dayton, OH 45435, USA.

American Journal of Cancer Research
|July 12, 2011
PubMed

Insights

The Fragile Histidine Triad (FHIT) gene, a tumor suppressor, is repressed by PI3K/AKT signaling in actively cycling cells. Removing growth factors derepresses FHIT, increasing its expression via FOXO transcription factors.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Gene Regulation

Background:

  • The Fragile Histidine Triad (FHIT) gene acts as a tumor suppressor in epithelial cells.
  • Mechanisms regulating FHIT gene expression are not well understood.
  • FHIT's role in tumor suppression is extensively studied, but its own regulation is less clear.

Purpose of the Study:

  • To investigate the regulation of FHIT gene expression.
  • To identify signaling pathways controlling FHIT expression in actively cycling cells.
  • To elucidate the role of PI3K/AKT/FOXO signaling in FHIT gene regulation.

Main Methods:

  • Cell culture experiments with growth factor stimulation and withdrawal.
  • Analysis of FHIT mRNA and protein levels.
  • Investigating the role of PI3K, AKT, and FOXO transcription factors.
  • RNA interference (RNAi) targeting FOXO family members in MCF7 breast carcinoma cells.

Main Results:

  • Phosphoinositide 3-kinase (PI3K) and AKT signaling suppress FHIT gene expression in response to growth factors.
  • Removal of mitogens leads to increased FHIT mRNA and protein levels.
  • AKT signaling regulates FHIT expression through FOXO transcription factors, specifically FOXO3a.
  • FHIT expression is dependent on FOXO3a in MCF7 cells.

Conclusions:

  • FHIT gene expression is actively repressed in cycling cells via the PI3K/AKT/FOXO3a pathway.
  • This study reveals a novel regulatory mechanism for the tumor suppressor FHIT.
  • Understanding FHIT regulation provides insights into cancer biology and potential therapeutic targets.
Keywords:
AKTFHITFOXOPI3Kmitogen signaling

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