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Grainyhead-like 2 Reverses the Metabolic Changes Induced by the Oncogenic Epithelial-Mesenchymal Transition: Effects

Joshua C Farris1, Phillip M Pifer1, Liang Zheng2

  • 1Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia.

Molecular Cancer Research : MCR
|April 17, 2016
PubMed
Abstract

Insights

Grainyhead-like 2 (GRHL2) reverses cancer-promoting EMT by altering cell metabolism. GRHL2 suppresses GLUD1, increasing ROS and restoring anoikis sensitivity, crucial for preventing tumor metastasis.

Area of Science:

  • Molecular and Cellular Oncology
  • Cancer Metabolism

Background:

  • Anoikis resistance is essential for tumor metastasis, and epithelial-to-mesenchymal transition (EMT) facilitates anoikis evasion.
  • Grainyhead-like 2 (GRHL2) is a transcription factor that suppresses EMT and cancer stem cell (CSC) phenotypes, restoring anoikis sensitivity.

Purpose of the Study:

  • To investigate the impact of GRHL2 on intracellular metabolism during EMT/CSC phenotype reversion.
  • To elucidate the mechanisms by which GRHL2 promotes anoikis sensitivity through metabolic reprogramming.

Main Methods:

  • Analysis of intracellular metabolism in cells undergoing EMT and GRHL2-mediated reversion.
  • Measurement of mitochondrial oxidative metabolism, reactive oxygen species (ROS) levels, and key metabolic enzymes like Glutamate dehydrogenase 1 (GLUD1).

Main Results:

  • EMT enhanced mitochondrial oxidative metabolism, increased superoxide, but decreased overall ROS by reducing hydrogen peroxide.
  • Glutamate dehydrogenase 1 (GLUD1) expression and its product α-ketoglutarate (α-KG) were elevated during EMT, protecting against anoikis.
  • GRHL2 suppressed GLUD1 expression, reduced α-KG, elevated ROS, and consequently sensitized cells to anoikis.

Conclusions:

  • GRHL2 promotes anoikis sensitivity by altering intracellular metabolism, specifically by suppressing GLUD1 and increasing ROS.
  • Metabolic reprogramming driven by GRHL2 offers a potential therapeutic strategy to inhibit tumor metastasis.

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