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Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions.

Teresa W-M Fan1, Jahid M M Islam2, Richard M Higashi1

  • 1Center for Environmental and System Biochemistry, University of Kentucky, Lexington, Kentucky, USA; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.

The Journal of Biological Chemistry
|November 22, 2023
PubMed
Summary

EZH2 suppression reduced lung cancer cell growth in 2D cultures but stimulated it in 3D, altering metabolic pathways. Extracellular matrix composition significantly impacts EZH2 inhibitor efficacy, crucial for in vivo modeling.

Keywords:
EZH2Stable isotope-resolved metabolomicsextracellular matrixglucose/glutamine metabolismspheroids

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Area of Science:

  • Cancer Biology
  • Epigenetics
  • Metabolomics

Background:

  • Enhancer of Zeste Homolog 2 (EZH2) is a key component of Polycomb Repressive Complex 2 (PRC2), regulating gene expression via histone methylation (H3K27me3).
  • EZH2 is overexpressed in lung cancers and has PRC2-independent functions, making it a therapeutic target, with EPZ-6438 (tazemetostat) being an FDA-approved inhibitor.
  • Understanding how the tumor microenvironment, including cell-cell and cell-matrix interactions in 3D systems, influences EZH2 inhibition is critical for effective cancer therapy.

Purpose of the Study:

  • To investigate the impact of EZH2 suppression on the growth and metabolic functions of human lung adenocarcinoma cells in 2D versus 3D culture systems.
  • To elucidate the metabolic underpinnings of EZH2 suppression's differential effects on cell growth.
  • To determine the role of PRC2-dependent and -independent functions and the influence of extracellular matrix (ECM) composition on EZH2 inhibition outcomes.

Main Methods:

  • Utilized stable isotope-resolved metabolomics with [13C6]-glucose to analyze metabolic network alterations in A549 cells with EZH2 suppression in 2D and 3D cultures.
  • Employed simultaneous 2H7-glucose + 13C5,15N2-Gln tracers and EPZ-6438 treatment to delineate PRC2-dependent metabolic effects.
  • Compared metabolic and growth responses in 3D cultures grown on mouse Matrigel versus self-produced A549 extracellular matrix.

Main Results:

  • EZH2 suppression reduced A549 cell growth in 2D cultures but stimulated it in 3D spheroids, correlating with metabolic changes.
  • In 3D spheroids, EZH2 suppression activated the Krebs cycle, neoribogenesis, gamma-aminobutyrate metabolism, and purine nucleotide salvage pathways, unlike in 2D cultures.
  • Metabolic effects on the Krebs cycle, gamma-aminobutyrate metabolism, gluconeogenesis, and purine salvage were confirmed as PRC2-dependent using EPZ-6438.
  • Significant differences in growth and metabolic outcomes were observed based on the type of extracellular matrix (Matrigel vs. self-produced ECM).

Conclusions:

  • EZH2 suppression has context-dependent effects on lung adenocarcinoma cell growth and metabolism, with 3D environments and ECM composition playing crucial roles.
  • Metabolic reprogramming, including Krebs cycle and purine salvage activation, is a key response to EZH2 suppression in 3D cultures and is PRC2-dependent.
  • The findings underscore the importance of considering the extracellular matrix in cancer models to accurately predict the in vivo efficacy of EZH2 inhibitors.